Compositions and methods for treating schizophrenia

ABSTRACT

The disclosure provides a novel polymorph of Compound (I): 
     
       
         
         
             
             
         
       
     
     2-((1-(2-(4-Fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one monohydrochloride dihydrate, i.e., Form (A) of Compound (I)-HCl-2H 2 O. Pharmaceutical compositions comprising Form (A) of Compound (I)-HCl-2H 2 O and related methods of treatment are also disclosed.

CROSS REFERENCES

This application is a continuation of U.S. application Ser. No.17/017,816, filed Sep. 11, 2020, which is a continuation of U.S.application Ser. No. 16/290,234, filed Mar. 1, 2019, now U.S. Pat. No.10,799,493, which is a continuation of U.S. application Ser. No.15/651,065, filed Jul. 17, 2017, now U.S. Pat. No. 10,258,614, which isa continuation of U.S. application Ser. No. 15/278,421, filed Sep. 28,2016, now U.S. Pat. No. 9,730,920, which is a continuation of U.S.application Ser. No. 14/954,264, filed Nov. 30, 2015, now U.S. Pat. No.9,458,130, which claims priority to, and the benefit of, U.S.Provisional Application No. 62/086,691, filed Dec. 2, 2014, and U.S.Provisional Application No. 62/248,071, filed Oct. 29, 2015, thecontents of each of which are incorporated herein by reference in theirentireties.

FIELD OF THE INVENTION

The present invention in some embodiments relates to compositions andmethods for treating schizophrenia in a patient.

BACKGROUND OF THE INVENTION

Schizophrenia is a complex, challenging, and heterogeneous psychiatriccondition, affecting up to 0.7% of the world population according to theWorld Health Organization (WHO, 2006). Patients suffering withschizophrenia present with a range of symptoms, including: positivesymptoms, such as delusions, hallucinations, thought disorders, andagitation; negative symptoms, such as mood flatness and lack of pleasurein daily life; cognitive symptoms, such as the decreased ability tounderstand information and make decisions, difficulty focusing, anddecreased working memory function; and sleep disorders.

The etiology of schizophrenia is not fully understood. A majorexplanatory hypothesis for the pathophysiology of schizophrenia is theDopamine (DA) hypothesis, which proposes that hyperactivity of DAtransmission is responsible for expressed symptoms of the disorder. Thishypothesis is based on the observation that drugs effective in treatingschizophrenia share the common feature of blocking DA D2 receptors.However, these so-called typical antipsychotics are associated with avery high incidence of extrapyramidal symptoms (EPS). Furthermore,negative symptoms and cognitive impairment are considered relativelyunresponsive to typical antipsychotics.

Most currently approved therapies for schizophrenia show efficacyprimarily in the management of positive symptoms. An estimated 4.2million people suffered from schizophrenia in 2012 in the United Statesand the five major European Union markets. Of those, an estimated 48%experienced predominantly negative symptoms and 80% suffered fromcognitive impairment. In addition, about 50% of patients withschizophrenia experience sleep disorders, which can further exacerbateboth positive and negative symptoms.

The introduction of the so-called atypical antipsychotics in the lastdecade represented a significant advance in the treatment ofschizophrenia. Although these atypical antipsychotics differ widely inchemical structure and receptor-binding profiles, they share acharacteristic of potent antagonism of the Serotonin(5-hydroxytryptamine) type 2 receptor (5-HT2A). A high 5-HT2A:D2affinity ratio is thought to substantially reduce the liability forinducing EPS, compared with typical antipsychotics.

However, many patients are still treatment-noncompliant despite theadvantage of atypical antipsychotics of tolerability. Although the riskof EPS is clearly lower with the atypical antipsychotics, the high dosesrequired with some atypical antipsychotics are likely to result in anincreased incidence of EPS and require concomitant medications such asantiparkinson drugs.

In addition to EPS, antipsychotic medications cause a broad spectrum ofside effects including sedation, anticholinergic effects, prolactinelevation, orthostatic hypotension, weight gain, altered glucosemetabolism, and QTc prolongation. These side effects can affectpatients' compliance with their treatment regimen. It should be notedthat noncompliance with treatment regimen is a primary reason forrelapse of the disease.

Although atypical antipsychotics offer advantages over typicalantipsychotics in terms of symptom alleviation and side effect profile,these differences are generally modest. A certain population of patientsstill remains refractory to all currently available antipsychotics.Newer agents to address these issues continue to be sought.

The disclosure provides compositions, methods, and kits to address thislong-felt and unmet need for a treatment for schizophrenia that iseffective for all subjects, particularly those who are not effectivelytreated by currently available therapies. The compositions, methods, andkits of the disclosure lead to greater patient compliance.

SUMMARY

The disclosure provides a novel polymorph of Compound (I),

(also known as MIN-101, CYR-101 and MT-210), which has showneffectiveness in animal models of psychosis (see also U.S. Pat. No.7,166,617, the contents of which are incorporated herein in theirentirety). Compound (I) is an antipsychotic drug belonging to a newchemical class, the cyclic amido derivatives. The chemical designationis2-((1-(2-(4-Fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-onemonohydrochloride dihydrate.

As used herein, the novel polymorph of Compound (I):

2-((1-(2-(4-Fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-onemonohydrochloride dihydrate, is also referred to as Form (A) of Compound(I)-HCl-2H₂O.

In one embodiment, Form (A) of Compound (I)-HCl-2H₂O is characterized byXRPD.

In one embodiment, Form (A) of Compound (I)-HCl-2H₂O is characterized byIR.

In one embodiment, Form (A) of Compound (I)-HCl-2H₂O is characterized by¹H NMR.

In one embodiment, Form (A) of Compound (I)-HCl-2H₂O is characterized by¹³C NMR.

The disclosure provides a process for preparing Form (A) of Compound(I)-HCl-2H₂O.

The disclosure provides pharmaceutical compositions comprising Form (A)of Compound (I)-HCl-2H₂O and a pharmaceutically acceptable diluent,excipient, or carrier.

The disclosure provides a method of treating a neuropsychiatric diseaseor disorder, comprising administering a therapeutically effective amountof Form (A) of Compound (I)-HCl-2H₂O or a pharmaceutical compositionthereof to a subject in need thereof.

The disclosure provides a method for treating schizophrenia, comprisingadministering a therapeutically effective amount of Form (A) of Compound(I)-HCl-2H₂O or a pharmaceutical composition thereof to a subject inneed thereof.

The disclosure relates to use of a pharmaceutical formulation of theinvention, in the manufacture of a medicament for treatingschizophrenia.

The disclosure provides a kit comprising a pharmaceutical compositioncomprising Form (A) of Compound (I)-HCl-2H₂O and instructions for use.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thedisclosure, suitable methods and materials are described below. Allpublications, patent applications, patents, and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed invention. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and are not intended to be limiting.

Other features and advantages of the disclosure will be apparent fromthe following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe invention, will be better understood when read in conjunction withthe appended drawings.

FIG. 1 is a graph illustrating plasma concentration—time profiles ofMIN-101.

FIG. 2 is a graph illustrating plasma concentration—time profiles ofBFB-520.

FIG. 3 is a graph illustrating plasma concentration—time profiles ofBFB-999.

FIG. 4 is a graph illustrating plasma concentrations of MIN-101,BFB-520, and BFB-999 by period.

FIG. 5 is a series of graphs illustrating the changes in QTcF byBFB-520, BFB-999, and CYR-101 concentrations.

FIG. 6 is a diagram illustrating a scheme of monitoring sleep using PSGand V-Watch.

FIG. 7 is a diagram illustrating Part 1 Study Design.

FIG. 8 is a diagram illustrating Part 2 Study Design.

FIG. 9 is a diagram illustrating Study Period Scheme.

FIG. 10 is a diagram illustrating Global Study Design for Phase IIB inpatients with schizophrenia.

FIG. 11 is an X-ray powder diffraction of Form (A) of Compound(I)-HCl-2H₂O.

FIG. 12 is an IR spectrum of Form (A) of Compound (I)-HCl-2H₂O.

FIG. 13 is a ¹H-NMR spectrum of Form (A) of Compound (I)-HCl-2H₂O.

FIG. 14 is a ¹³C-NMR spectrum of Form (A) of Compound (I)-HCl-2H₂O.

FIG. 15 is an IR spectrum comparison between batch C001 and V039SS(secondary reference standard from MTPC).

FIG. 16 is a ¹H-NMR spectrum of batch C001 (from PCAS).

FIG. 17 is a ¹³C-NMR spectrum for batch C001 (from PCAS).

FIG. 18 is a mass spectrum of Form (A) of Compound (I)-HCl-2H₂O byMALDI-TOF (from MTPC).

FIG. 19 is a mass spectrum of Form (A) of Compound (I)-HCl-2H₂O by ESIionization for bath C001 (from PCAS).

DETAILED DESCRIPTION OF THE INVENTION

The disclosure provides compositions, methods, and kits for thetreatment of a neuropsychiatric disease or condition. Preferably theneuropsychiatric disease or condition is schizophrenia. Compositions andkits of the disclosure include pharmaceutical compositions. Compositionsof the disclosure comprise a stable polymorph of Compound (I)-HCl-2H₂O,which is preferably Form (A) of Compound (I)-HCl-2H₂O.

Form A of Compound (I)

The disclosure pertains, at least in part, to a stable polymorph ofCompound (I)-HCl-2H₂O.

In one embodiment, the polymorph of Compound (I)-HCl-2H₂O is Form (A).

In one embodiment, Form (A) of Compound (I)-HCl-2H₂O has an X-ray powderdiffraction pattern substantially similar to that shown in FIG. 11 .

In one embodiment, Form (A) of Compound (I)-HCl-2H₂O has X-ray powderdiffraction peaks at approximately 7.6 and 14.3°2θ using Cu Kαradiation.

In one embodiment, Form (A) has X-ray powder diffraction peaks atapproximately 7.6, 14.3, and 14.7°2θ using Cu Kα radiation.

In one embodiment, Form (A) has X-ray powder diffraction peaks atapproximately 7.6, 14.3, and 27.5°2θ using Cu Kα radiation.

In one embodiment, Form (A) has X-ray powder diffraction peaks atapproximately 7.6, 14.3, 14.7, and 27.5°2θ using Cu Kα radiation.

In one embodiment, Form (A) has X-ray powder diffraction peaks atapproximately 7.6, 14.3, 14.7, 18.6, and 27.5°2θ using Cu Kα radiation.

In one embodiment, Form (A) has X-ray powder diffraction peaks atapproximately 7.6, 14.3, 14.7, 14.9, 18.6, 27.5 and 30.1°2θ using Cu Kαradiation.

In one embodiment, Form (A) has X-ray powder diffraction peaks atapproximately 7.6, 11.2, 14.3, 14.7, 14.9, 18.6, 22.0, 25.9, 27.5 and30.1° 2θ using Cu Kα radiation.

In one embodiment, Form (A) of Compound (I)-HCl-2H₂O has an IRabsorption spectrum substantially similar to that shown in FIG. 12 .

In one embodiment, Form (A) has an IR absorption spectrum with a mainwave number of absorption at 2916 cm⁻¹.

In one embodiment, Form (A) has an IR absorption spectrum with a mainwave number of absorption at 1684 cm⁻¹.

In one embodiment, Form (A) has an IR absorption spectrum with a mainwave number of absorption at 1665 cm⁻¹.

In one embodiment, Form (A) has an IR absorption spectrum with a mainwave number of absorption at 1594 cm⁻¹.

In one embodiment, Form (A) has an IR absorption spectrum with a mainwave number of absorption at 1235 cm⁻¹.

In one embodiment, Form (A) has an IR absorption spectrum with a mainwave number of absorption at 1684 and 1665 cm⁻¹.

In one embodiment, Form (A) has an IR absorption spectrum with main wavenumbers of absorption at 2916, 1684, and 1665 cm⁻¹.

In one embodiment, Form (A) has an IR absorption spectrum with main wavenumbers of absorption at 2916, 1684, and 1665 cm⁻¹.

In one embodiment, Form (A) has an IR absorption spectrum with main wavenumbers of absorption at 2916, 1594, and 1235 cm⁻¹.

In one embodiment, Form (A) has an IR absorption spectrum with main wavenumbers of absorption at 2916, 1684, 1665, and 1235 cm⁻¹.

In one embodiment, Form (A) has an IR absorption spectrum with main wavenumbers of absorption at 2916, 1684, 1665, 1594, and 1235 cm⁻¹.

In one embodiment, Form (A) of Compound (I)-HCl-2H₂O has a ¹H NMRspectrum substantially similar to that shown in FIG. 13 .

In one embodiment, Form (A) of Compound (I)-HCl-2H₂O has a ¹³C NMRspectrum substantially similar to that shown in FIG. 14 .

In one embodiment, Form (A) has ¹³C NMR spectrum peaks at 164.7, 166.7,167.6, and 190.1 δ in d₆-dimethyl sulfoxide.

In one embodiment, Form (A) has ¹³C NMR spectrum peaks at 60.6, 164.7,166.7, 167.6, and 190.1 δ in d₆-dimethyl sulfoxide.

In one embodiment, Form (A) has ¹³C NMR spectrum peaks at 50.2, 60.6,164.7, 166.7, 167.6, and 190.1 δ in d₆-dimethyl sulfoxide.

In one embodiment, Form (A) has ¹³C NMR spectrum peaks at 46.5, 50.2,60.6, 164.7, 166.7, 167.6, and 190.1 δ in d₆-dimethyl sulfoxide.

The application also pertains, at least in part, to a process forpreparing a polymorph of Compound (I)-HCl-2H₂O.

In one embodiment, the disclosure pertains to a process for making Form(A) of Compound (I)-HCl-2H₂O.

In one embodiment, Form (A) of Compound (I)-HCl-2H₂O is prepared by aprocess comprising: (1) reaction of the free base of Compound (I) withhydrochloric acid in acetone; and (2) heating of the crude Compound (I)in acetone and water, followed by cooling, filtration, and drying underreduced pressure.

The disclosure also pertains, at least in part, to a process forpreparing a highly pure form of a polymorph of Compound (I)-HCl-2H₂O. Inone embodiment, the highly pure form of a polymorph of Compound(I)-HCl-2H₂O is Form (A). In one embodiment, Form (A) has a purity of atleast 90%. In one embodiment, Form (A) has a purity of at least 92%. Inone embodiment, Form (A) has a purity of at least 94%. In oneembodiment, Form (A) has a purity of at least 95%. In one embodiment,Form (A) has a purity of at least 96%. In one embodiment, Form (A) has apurity of at least 97%. In one embodiment, Form (A) has a purity of atleast 98%. In one embodiment, Form (A) has a purity of at least 99%. Inone embodiment, Form (A) has a purity of at least 99.5%. In oneembodiment, Form (A) has a purity of at least 99.6%. In one embodiment,Form (A) has a purity of at least 99.7%. In one embodiment, Form (A) hasa purity of at least 99.8%.

The disclosure also pertains, at least in part, to a process forpreparing a polymorph form of Compound (I)-HCl-2H₂O with minimal amountsof impurities. In one embodiment, the polymorph form of Compound(I)-HCl-2H₂O with minimal amounts of impurities is Form (A). In oneembodiment, the form of a polymorph of Compound (I)-HCl-2H₂O withminimal amounts of impurities is Form (A), wherein the impurities are(V),

In one embodiment, Form (A), contains less than 3% combined ofimpurities (V), (VI), and (VII). In one embodiment, Form (A), containsless than 2.5% combined of impurities (V), (VI), and (VII). In oneembodiment, Form (A), contains less than 2% combined of impurities (V),(VI), and (VII). In one embodiment, Form (A), contains less than 1.5%combined of impurities (V), (VI), and (VII). In one embodiment, Form(A), contains less than 1% combined of impurities (V), (VI), and (VII).In one embodiment, Form (A), contains less than 0.5% combined ofimpurities (V), (VI), and (VII).

In another embodiment, Form (A) contains less than 0.5% of impurity (V).In another embodiment, Form (A) contains less than 0.2% of impurity (V).In another embodiment, Form (A) contains less than 0.1% of impurity (V).

In another embodiment, Form (A) contains less than 1% of impurity (VI).In another embodiment, Form (A) contains less than 0.5% of impurity(VI). In another embodiment, Form (A) contains less than 0.2% ofimpurity (VI). In another embodiment, Form (A) contains less than 0.1%of impurity (VI).

In another embodiment, Form (A) contains less than 1% of impurity (VII).In another embodiment, Form (A) contains less than 0.5% of impurity(VII). In another embodiment, Form (A) contains less than 0.2% ofimpurity (VII). In another embodiment, Form (A) contains less than 0.1%of impurity (VII).

The disclosure also pertains to pharmaceutical compositions comprising apolymorph of Compound (I)-HCl-2H₂O and one or more pharmaceuticallyacceptable diluents, excipients, or carriers. In one embodiment, thepharmaceutical compositions comprise Form (A) of Compound (I)-HCl-2H₂Oand one or more pharmaceutically acceptable diluents, excipients, orcarriers.

The disclosure also pertains to a method of treating a neuropsychiatricdisease or disorder, comprising administering a therapeuticallyeffective amount of a polymorph of Compound (I)-HCl-2H₂O or apharmaceutical composition thereof to a subject in need thereof.

In one embodiment, the disclosure also pertains to a method of treatinga neuropsychiatric disease or disorder, comprising administering atherapeutically effective amount of Form (A) of Compound (I)-HCl-2H₂O,or a pharmaceutical composition thereof, to a subject in need thereof.

In one embodiment, the neuropsychiatric disease is schizophrenia.

The term “polymorph” is synonymous with “crystalline polymorph”,“crystal polymorph”, “crystal form” and “polymorphic form.” Each termrefers to a crystal structure in which Compound (I)-HCl-2H₂Ocrystallizes in a specific crystal packing arrangements, i.e., Form (A),which has the same elemental composition as Compound (I)-HCl-2H₂O.

The differences in physical properties exhibited by polymorphs affectpharmaceutical parameters such as storage stability, compressibility anddensity (important in formulation and product manufacturing), anddissolution rates (an important factor in bioavailability). Differencesin stability can also result from changes in chemical reactivity (e.g.,differential oxidation, such that a dosage form discolors more rapidlywhen comprised of one polymorph than when comprised of another polymorphor amorphous form) or mechanical property (e.g., tablets crumble onstorage as a kinetically favored polymorph or amorphous form converts tothermodynamically more stable polymorph or amorphous form) or both(e.g., tablets of one polymorph or amorphous form are more susceptibleto breakdown at high humidity). In addition, the physical properties ofthe crystal may be important in processing, for example, a polymorph oramorphous form might be more likely to form solvates or might bedifficult to filter and wash free of impurities (e.g., particle shapeand size distribution might be different between a polymorph and anamorphous form).

A polymorph of a molecule can be obtained by a number of methods, asknown in the art. Such methods include, but are not limited to, meltrecrystallization, melt cooling, solvent recrystallization, desolvation,rapid evaporation, rapid cooling, slow cooling, vapor diffusion, andsublimation.

Techniques for characterizing polymorphs include, but are not limitedto, differential scanning calorimetry (DSC), X-ray powder diffractometry(XRPD), single crystal X-ray diffractometry, vibrational spectroscopy(e.g., IR and Raman spectroscopy), TGA, DTA, DVS, solid state NMR, hotstage optical microscopy, scanning electron microscopy (SEM), electroncrystallography and quantitative analysis, particle size analysis (PSA),surface area analysis, solubility studies, and dissolution studies.

As used herein, the term “amorphous form” refers to a noncrystallinesolid state form of a substance.

As used herein, a compound is “stable” where significant amounts ofdegradation products are not observed under constant conditions ofhumidity (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%,and 95% relative humidity, light exposure and temperatures (e.g., higherthan 0° C., e.g., 20° C., 25° C., 30° C., 35° C., 40° C., 45° C., 50°C., 55° C., 60° C., 65° C., and 70° C.) over a certain period (e.g., oneweek, two weeks, three weeks, and four weeks). A compound is notconsidered to be stable at a certain condition when degradationimpurities appear or an area percentage (e.g., AUC as characterized byHPLC) of existing impurities begins to grow. The amount of degradationgrowth as a function of time is important in determining compoundstability.

As used herein, the term “mixing” means combining, blending, stirring,shaking, swirling, or agitating. The term “stirring” means mixing,shaking, agitating, or swirling. The term “agitating” means mixing,shaking, stirring, or swirling.

Unless explicitly indicated otherwise, the terms “approximately” and“about” are synonymous. In one embodiment, “approximately” and “about”refer to recited amount, value, or duration ±20%, 15%,10%,±8%,±6%,±5%,±4%,±2%, ±1%, or 0.5%. In another embodiment,“approximately” and “about” refer to listed amount, value, orduration+10%, +8%,±6%, ±5%, ±4%, or ±2%. In yet another embodiment,“approximately” and “about” refer to listed amount, value, or duration±5%.

When the terms “approximately” and “about” are used when reciting XRPDpeaks, these terms refer to the recited X-ray powder diffractionpeak±0.5°2θ,±0.4°2θ±0.3°2θ, ±0.2°2θ, or ±0.1°2θ. In another embodiment,the terms “approximately” and “about” refer to the listed X-ray powderdiffraction peak±0.2°2θ. In another embodiment, the terms“approximately” and “about” refer to the listed X-ray powder diffractionpeak±0.1°2θ.

When the terms “approximately” and “about” are used when recitingtemperature or temperature range, these terms refer to the recitedtemperature or temperature range±5° C., ±2° C., or ±1° C. In anotherembodiment, the terms “approximately” and “about” refer to the recitedtemperature or temperature range ±2° C.

Compound (I)

The disclosure provides pharmaceutical formulations of Compound (I):

or a pharmaceutically acceptable salt thereof.

In one embodiment, the formulations of the disclosure provide maximumplasma concentration (C_(max)) and area under the curve (AUC) ofCompound (I) and its two active metabolites (BFB-520 and BFB-999) atlevels associated with improved therapeutic response and fewer adversereactions (e.g., prolongation of QT intervals).

In one embodiment, the formulations of the disclosure increase themaximum plasma concentration (C_(max)) and area under the curve (AUC) ofBFB-999 and at the same time reduce the maximum plasma concentration(C_(max)) and area under the curve (AUC) of BFB-520.

In one embodiment, the formulations of the disclosure provide a maximumplasma concentration (C_(max)) of Compound (I) below 50 ng/mL, below 45ng/mL, below 40 ng/mL, below 35 ng/mL, below 30 ng/mL, below 25 ng/mL,below 20 ng/mL, below 15 ng/mL, or below 10 ng/mL. In one embodiment,the formulations of the disclosure provide an AUC of Compound (I) below400 hr*ng/mL, below 350 hr*ng/mL, below 300 hr*ng/mL, below 250hr*ng/mL, below 200 hr*ng/mL, below 150 hr*ng/mL, or below 100 hr*ng/mL.

In one embodiment, the formulations of the disclosure provide a maximumplasma concentration (C_(max)) of BFB-520 below 5.0 ng/mL, below 4.5ng/mL, below 4.0 ng/mL, below 3.5 ng/mL, below 3.0 ng/mL, below 2.5ng/mL, below 2.0 ng/mL, below 1.5 ng/mL, or below 1.0 ng/mL. In oneembodiment, the formulations of the disclosure provide an AUC of BFB-520below 40 hr*ng/mL, below 35 hr*ng/mL, below 30 hr*ng/mL, below 25hr*ng/mL, below 20 hr*ng/mL, below 15 hr*ng/mL, or below 10 hr*ng/mL. Inone embodiment, BFB-520 is associated with prolongation of QT intervalsat supra-therapeutic levels.

In one embodiment, to avoid QT prolongation, maximum plasmaconcentration (C_(max)) of Compound (I) and BFB-520 should not exceed 80ng/mL and 12 ng/mL respectively. In one embodiment, the formulations ofthe disclosure provide a C_(max) of BFB-520 below 10 ng/mL, below 9.0ng/mL, below 8.0 ng/mL, below 7.0 ng/mL, below 6.0 ng/mL, 5.0 ng/mL,below 4.5 ng/mL, below 4.0 ng/mL, below 3.5 ng/mL, below 3.0 ng/mL,below 2.5 ng/mL, below 2.0 ng/mL, below 1.5 ng/mL, or below 1.0 ng/mL.In one embodiment, the formulations of the disclosure provide a C_(max)of BFB-999 below 5.0 ng/mL, below 4.5 ng/mL, below 4.0 ng/mL, below 3.5ng/mL, below 3.0 ng/mL, below 2.5 ng/mL, below 2.0 ng/mL, below 1.5ng/mL, or below 1.0 ng/mL. In one embodiment, the formulations of thedisclosure provide an AUC of BFB-999 below 40 hr*ng/mL, below 35hr*ng/mL, below 30 hr*ng/mL, below 25 hr*ng/mL, below 20 hr*ng/mL, below15 hr*ng/mL, or below 10 hr*ng/mL.

In one embodiment, the formulations of the disclosure comprise about1-100 mg of Compound (I), about 1-75 mg of Compound (I), about 2-75 mgof Compound (I), about 5-75 mg of Compound (I), about 10-75 mg ofCompound (I), about 15-75 mg of Compound (I), about 15-70 mg of Compound(I), about 15-65 mg of Compound (I). In one embodiment, the formulationsof the disclosure comprise about 16 mg of Compound (I), about 32 mg ofCompound (I), about 40 mg of Compound (I), or about 64 mg of Compound(I).

In one embodiment, the formulations of the disclosure are suitable forchronic administration (e.g., one week, two weeks, three weeks, fourweeks, two months, four months, six months, eight months, ten months,one year, two years, three years, four years, and five years).

In one embodiment, the formulations of the disclosure are administeredonce daily.

In one embodiment, the formulations of the disclosure are administeredto a subject under a fast condition. In one embodiment, the formulationsof the disclosure are administered to a subject at least 4 hours afterthe subject has taken a meal, at least 6 hours after the subject hastaken a meal, at least 8 hours after the subject has taken a meal, atleast 10 hours after the subject has taken a meal, at least 12 hoursafter the subject has taken a meal. In one embodiment, the formulationsof the disclosure are administered to a subject under a fed condition.In one embodiment, the formulations of the disclosure are administeredto a subject within 4 hour after the subject has taken a meal, within 3hours after the subject has taken a meal, within 2 hours after thesubject has taken a meal, within 1 hour after the subject has taken ameal, or within 0.5 hour after the subject has taken a meal.

By “a meal” it means any amount of food, which includes any sources ofcarbohydrate, protein, amino acid, etc.

In one embodiment, the formulations of the disclosure are suitable fororal administration, intravenous administration, intramuscularadministration, or subcutaneous administration. In one embodiment, theformulations of the disclosure are suitable for oral administration. Inone embodiment, the formulations of the disclosure are in the form of atablet or capsule.

In one embodiment, the tablet formulation comprises Compound (I), arelease modifier, a filler, a glidant, and a lubricant. In oneembodiment, the release modifier is hypromellose (e.g., hypromelloseK100LV CR, hypromellose K4M CR, hypromellose E50, or a combinationthereof). In one embodiment, the filler is microcrystalline cellulose,lactose, or a combination thereof. In one embodiment, the glidant issilica colloidal anhydrous. In one embodiment, the lubricant ismagnesium stearate, Kolliwax HCO, sodium stearyl fumarate, or acombination thereof.

In a further embodiment, the tablet formulation may further comprise abinder, such as hydroxypropylcellulose. In a further embodiment, thetablet formulation may further comprise a disintegrant, such ascrospovidone. In a further embodiment, the tablet formulation mayfurther comprise an anti-adherent, such as talc. In a furtherembodiment, the tablet formulation may further comprise a pH adjuster,such as an organic or inorganic acid or an organic or inorganic base. Ina further embodiment, the tablet formulation may further comprisesweeting agent, such a sugar (e.g., mannitol).

In one embodiment, the release profile of the tablet formulation iscontrolled by varying the amount of the release modifier in theformulation. In one embodiment, the release rate of Compound (I) fromthe tablet formulation is decreased by increasing the amount of therelease modifier.

In one embodiment, the formulations of the disclosure are in animmediate release form. In one embodiment, the formulations of thedisclosure are in a modified release form. In one embodiment, themodified release formulations are in a slow-(release rate of 16-24hours), medium-(release rate of 10-12 hours) or fast-(release rate of5-7 hours) release form.

In one embodiment, the formulations of the disclosure are in acontrolled release form.

In one embodiment, the formulations of the disclosure are in a sustainedrelease form (e.g., the release takes place for at least 4 hours, 6hours, 8 hours, 10 hours, 12 hours, 18 hours, or 24 hours). In oneembodiment, the formulations of the disclosure are in the form of a slowsustained release form.

The disclosure also relates to methods for treating neuropsychiatricdiseases and disorders, in particular, schizophrenia, comprisingadministering a therapeutically effective amount of a formulation of theinvention to a subject in need thereof.

In one embodiment, a method for treating or diminishing at least onesymptom of neuropsychiatric diseases and disorders, in particular,schizophrenia, is provided, comprising administering a therapeuticallyeffective amount of a formulation of the invention to a subject in needthereof.

In one embodiment, a method for treating or diminishing at least onesymptom of schizophrenia is provided, comprising administering atherapeutically effective amount of a formulation of the invention to asubject in need thereof.

In one embodiment, a method for treating or diminishing at least onesymptom of schizophrenia is provided, comprising administering aformulation of the invention to a subject in need thereof, wherein theamount of Compound (I) is in the range of about 1-100 mg, about 1-75 mg,about 2-75 mg, about 5-75 mg, about 10-75 mg, about 15-75, about 15-70mg, or about 15-65 mg.

In one embodiment, a method for treating or diminishing at least onesymptom of schizophrenia is provided, comprising administering aformulation of the invention to a subject in need thereof, wherein theamount of Compound (I) is about 16 mg, about 32 mg, about 40 mg, orabout 64 mg.

In one embodiment, the formulations of the disclosure are administeredfor treating or diminishing at least one symptom of schizophreniaassociated with the negative and/or positive symptoms of schizophrenia,cognitive function, sleep architecture and continuity, and socialfunctioning.

In another embodiment, the formulations of the disclosure areadministered for improving depressive symptoms.

In one embodiment, a method for treating or diminishing at least onecondition or disorder associated with depression is provided, comprisingadministering a formulation of the invention to a subject in needthereof.

In another embodiment, a method for improving sleep, such as sleeparchitecture and continuity, is provided, comprising administering aformulation of the invention to a subject in need thereof.

In one embodiment, a method for treating or diminishing at least oneaspect of a sleep disorder in a subject afflicted with neuropsychiatricdiseases and disorders, in particular, schizophrenia, is provided,comprising administering a formulation of the invention to the subject.

In one embodiment, at least one aspect of a sleep disorder is treated.In another embodiment, at least one aspect of a sleep disorder isimproved. In an aspect, the disruption of at least one aspect of sleepis associated with schizophrenia.

Various aspects of sleep may be treated, including, but not limited to,sleep onset latency, latency to persistent sleep, distribution of slowwave sleep across the sleep period time, or one or more segments ofsleep period time, overall sleep continuity and sleep architecture.

Cognitive impairment is the diminished ability to think, concentrate,formulate ideas, reason and remember. In one embodiment, a method fortreating or diminishing cognitive impairment or improving cognition isprovided, comprising administering a formulation of the invention to asubject in need thereof. In one embodiment, a method is provided fortreating schizophrenia without provoking cognitive impairment.

In one embodiment, a method is provided for treating schizophrenia andrestoring, enhancing, and improving cognition, in a subject followingdiscontinuation of treatment with another active pharmaceuticalingredient, for example, an anti-depressant compound.

In one embodiment, a method is provided for treating schizophrenia incombination with a cognition impairing active pharmaceutical ingredient(for example, a cognition impairing anti-depressant compound), withoutcausing or increasing cognitive impairment, or for improving, enhancingor restoring cognition in a subject.

In another embodiment, cognitive impairment present in a subjectsuffering from schizophrenia is treated or diminished by theadministration of a formulation of the invention to the subject. As willbe understood based on the disclosure herein, modification of sleepparameters can improve cognition. By way of a non-limiting example,improvement and/or an increase in slow wave sleep (SWS) improvescognition. In an aspect, cognition in general is improved. In anotheraspect, one or more aspects of cognition are improved, including, amongothers, memory consolidation, executive functions, verbal memory, andverbal fluency. In one embodiment, cognition is improved in a subject tothe point where normal cognition is restored in the subject. In anotherembodiment, cognition is improved in a subject beyond the point ofnormal cognition in the subject, such that levels of cognition in thesubject are enhanced.

In one embodiment, cognition is improved in a subject afflicted withschizophrenia.

The active ingredient is Compound (I) (also known as CYR-101 andMT-210). U.S. Pat. No. 7,166,617, incorporated herein by reference inits entirety, discloses cyclic amide derivatives including Compound (I),2-{1-[2-(4-Fuorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindol-1-onemonohydrochloride dihydrate. The derivatives disclosed in U.S. Pat. No.7,166,617 were found to have high affinity for the sigma ligand bindingsite and low inhibition constant Ki for sigma 1 and/or sigma 2. It wasalso found that these compounds had a selective binding profilecompletely different from those of conventional known compounds, andwere useful for treatment of diseases that can be therapeutically and/orpreventively treated by the nerve control function of the sigma ligands.

The formulations of Compound (I) as described herein represent animportant milestone in an effort to develop customized formulations ofneuropsychiatric therapies based on optimal efficacy, safety,tolerability and pharmacokinetic profiles. The formulations as describedherein are able to target significant areas of unmet need in thetreatment of negative symptoms, cognitive impairments and sleepdisorders while offering a highly favorable safety profile.

The formulations of the disclosure are able to maintain plasma levels ofCompound (I) over the course of one day while reducing BFB-520 levelsand increasing levels of BFB-999 associated with sleep improvements dueto its affinity to 5-HT2A and histaminergic H1 receptors. It is shownthat the formulations of the disclosure lower levels of BFB-520, whichis associated with prolongation of QT intervals at supra-therapeuticlevels.

The QT interval represents the duration of ventricular depolarizationand subsequent repolarization, and is measured from the beginning of theQRS complex to the end of the T wave. A delay in cardiac repolarizationcreates an electrophysiological environment that favors the developmentof cardiac arrhythmias, most clearly torsade de pointes (TdP), butpossibly other ventricular tachyarrhythmias as well. TdP is apolymorphic ventricular tachyarrhythmia that appears on the ECG ascontinuous twisting of the vector of the QRS complex around theisoelectric baseline. A feature of TdP is pronounced prolongation of theQT interval in the supraventricular beat preceding the arrhythmia. TdPcan degenerate into ventricular fibrillation, leading to sudden death.According to ICH-E14 on Clinical Evaluation of QT/QTc IntervalProlongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs,discontinuation of a subject from a clinical trial should be consideredif there is a marked prolongation of the QT/QTc interval duringtreatment with the study drug, especially if the measurement is obtainedfrom more than one ECG.

The disclosure provides an optimal formulation which reduces the risk ofQT/QTc prolongation and achieves a once a day dosing strategy tofacilitate patient compliance.

Definitions

In other embodiments, as set forth in greater detail elsewhere herein,the dosage and dosing regimen for Compound (I) and/or Form A of Compound(I) may be optimized based on the health and condition of the subject tobe treated, as well as the desired outcome of the treatment.

The term “receptor”, as used herein, means a molecule, with which one ormore kinds of signaling molecules can specifically interact. Forexample, the 5-HT1A receptor is a subtype of the 5-HT receptor, whichbinds the neurotransmitter serotonin (“5-hydroxytryptamine”).

The term “subject” refers to any animal, including mammals, such as, butnot limited to, humans, mice, rats, other rodents, rabbits, dogs, cats,pigs, cattle, sheep, horses, or primates.

The term “treating” (and corresponding terms “treat” and “treatment”)includes palliative, restorative, and preventative (“prophylactic”)treating of a subject. The term “palliative treating” refers totreatment that eases or reduces the effect or intensity of a conditionin a subject without curing the condition. The term “preventativetreating” (and the corresponding term “prophylactic treating”) refers totreatment that prevents the occurrence of a condition in a subject.

The term “restorative treating” (“curative”) refers to treatment thathalts the progression of, reduces the pathologic manifestations of, orentirely eliminates a condition in a subject. Treating can be done witha therapeutically effective amount of compound, salt or composition thatelicits the biological or medicinal response of a tissue, system orsubject that is being sought by an individual such as a researcher,doctor, veterinarian, or clinician. The term “treatment” will also beunderstood to include not only a complete remission of all symptomsexperienced by the treated individual, but also the alleviation of oneor more existing symptoms, as well as the prevention of occurrence ofsymptoms by preemptive administration of a compound of formula I to anindividual prone to or likely to develop any of the symptoms, such asthose with chronic or recurrent neuropsychiatric disease or disorder.

The term “modified release” as used herein can be understood as theescape of the drug from the tablet has been modified in some way.Usually this is to slow the release of the drug so that the medicinedoes not have to be taken too often and therefore improves compliance.The other benefit from modifying release is that the drug release iscontrolled and there are smaller peaks and troughs in blood levelstherefore reducing the chance of peak effects and increasing thelikelihood of therapeutic effectiveness for longer periods of time.

The pattern of drug release from modified-release (MR) dosage forms isdeliberately changed from that of a conventional (immediate-release)dosage formulation to achieve a desired therapeutic objective or betterpatient compliance. Types of MR drug products may include delayedrelease (e.g., enteric coated), extended release (ER), and orallydisintegrating tablets (ODT).

The term modified-release formulation can be used to describeformulation that alters the timing and/or the rate of release of thedrug substance. A modified-release dosage form is a formulation in whichthe drug-release characteristics of time course and/or location arechosen to accomplish therapeutic or convenience objectives not offeredby conventional dosage forms such as solutions, ointments, or promptlydissolving dosage forms. Several types of modified-release oral drugproducts are recognized including:

An extended-release formulation refers to a formulation that allows atleast a two-fold reduction in dosage frequency as compared to animmediate-release (conventional) dosage form. Examples ofextended-release dosage forms include controlled-release,sustained-release, and long-acting drug products.

A delayed-release formulation refers to a formulation that releases adiscrete portion or portions of drug at a time other than promptly afteradministration. An initial portion may be released promptly afteradministration. Enteric-coated dosage forms are common delayed-releaseproducts (e.g., enteric-coated aspirin and other NSAID products).

The term “compounds of the disclosure” of “compound of the disclosure”refers to Compound (I), Form A of Compound (I) or a pharmaceuticallyacceptable salt thereof as described herein.

The term “pharmaceutically acceptable”, as used herein with respect to acompound or composition, refers to a form of the compound or compositionthat can increase or enhance the solubility or availability of thecompound in a subject, in order to promote or enhance thebioavailability of the compound or composition.

The term “pharmaceutically acceptable salt” is to describe a salt formof one or more of the compositions herein which are presented toincrease the solubility of the compound, for example, in the gastricjuices of the patient's gastrointestinal tract in order to promotedissolution and the bioavailability of the compounds and/orcompositions. In an embodiment, pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids. Suitable salts include those derived fromalkali metals such as potassium and sodium, alkaline earth metals suchas calcium, magnesium and ammonium salts, among numerous other acidswell known in the pharmaceutical art. Sodium and potassium salts areparticularly preferred as neutralization salts of carboxylic acids andfree acid phosphate containing compositions encompassed by the presentdisclosure. The term “salt” shall mean any salt consistent with the useof the compounds encompassed by the present disclosure. In the casewhere the compounds are used in pharmaceutical indications, includingthe treatment of depression, the term “salt” shall mean apharmaceutically acceptable salt, consistent with the use of thecompounds as pharmaceutical agents.

As used herein, the term pharmaceutically acceptable salts refer tosalts that retain the desired biological activity of the parent compoundand exhibit minimal, if any, undesired toxicological effects.Nonlimiting examples of such salts are (a) acid addition salts formedwith inorganic acids (for example, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and the like), and saltsformed with organic acids such as acetic acid, oxalic acid, tartaricacid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannicacid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonicacids, naphthalenedisulfonic acids, and polygalacturonic acid; (b) baseaddition salts formed with polyvalent metal cations such as zinc,calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel,cadmium, sodium, potassium, and the like, or with an organic cationformed from N,N-dibenzylethylene-diamine, ammonium, or ethylenediamine;or (c) combinations of (a) and (b); e.g., a zinc tannate salt or thelike.

In an embodiment, compositions comprise base addition salts of thepresent compound. The chemical bases that may be used as reagents toprepare pharmaceutically acceptable base salts of the present compoundsthat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto those derived from such pharmacologically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine (meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines, among others.

A “composition” or “pharmaceutically acceptable composition” is aformulation containing a compound of the invention or salt, solvate,ester, or amino acid conjugate thereof. In one embodiment, thepharmaceutical composition is in bulk or in unit dosage form. The unitdosage form is any of a variety of forms, including, for example, acapsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or avial. The quantity of active ingredient (e.g., a formulation of acompound of the invention or salts thereof) in a unit dose ofcomposition is an effective amount and is varied according to theparticular treatment involved. One skilled in the art will appreciatethat it is sometimes necessary to make routine variations to the dosagedepending on the age and condition of the patient. The dosage will alsodepend on the route of administration. A variety of routes arecontemplated, including oral, ocular, ophthalmic, pulmonary, rectal,parenteral, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal, intranasal, and the like. Dosage forms for the topicalor transdermal administration of a compound of this invention includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. In another embodiment, the active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that arerequired.

In certain embodiments, the pharmaceutical formulations or compositionsof the present invention may additionally contain other adjunctcomponents conventionally found in pharmaceutical compositions, at theirart-established usage levels. Thus, for example, the compositions maycontain additional materials useful in physically formulating variousdosage forms of the compositions of the present invention, such as dyes,flavoring agents, preservatives, antioxidants, opacifiers, thickeningagents and stabilizers. However, such materials, when added, should notunduly interfere with the biological activities of the components of thecompositions of the present invention. The formulations can besterilized and, if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringsand/or aromatic substances and the like which do not deleteriouslyinteract with the oligonucleotide(s) of the formulation.

In certain embodiments, pharmaceutical compositions of the presentinvention comprise one or more excipients. In certain such embodiments,excipients are selected from water, salt solutions, alcohol,polyethylene glycols, gelatin, lactose, amylase, magnesium stearate,talc, silicic acid, viscous paraffin, hydroxymethylcellulose andpolyvinylpyrrolidone.

In certain embodiments, a pharmaceutical composition of the presentinvention is prepared using known techniques, including, but not limitedto mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or tableting processes.

Modifications of a compound can affect the solubility, bioavailabilityand rate of metabolism of the active species, thus providing controlover the delivery of the active species. Further, the modifications canaffect the desired activity of the compound, in some cases increasingthe activity over the parent compound. This can easily be assessed bypreparing the derivative and testing its antidepressant activityaccording to the methods encompassed herein, or other methods known tothose skilled in the art.

Compositions encompassed herein may be administered orally. In otherembodiments, compositions may be administered parenterally, byinhalation spray, topically, rectally, nasally, buccally, vaginally orvia an implanted reservoir. The term “parenteral” as used hereinincludes subcutaneous, percutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. As will be understood by the skilled artisan, in view of theembodiments encompassed herein, the means of administration and thedosage of active ingredient or ingredients (e.g., a compound of formulaI) may be adjusted upward or downward based on the selected route ofadministration. Furthermore, it will be understood that optimizing thedosage of active ingredient for any selected dosage form may be desiredand can be achieved by using the methods described herein or known inthe art to evaluate the effectiveness of antipsychotic compounds.

The pharmaceutical compositions embodied herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. In an embodiment, lubricating agents, such asmagnesium stearate, are also added. For oral administration in a capsuleform, useful diluents include lactose and/or dried corn starch, as twonon-limiting examples. When aqueous suspensions are required for oraluse, the active ingredient is combined with emulsifying and suspendingagents. If desired, certain sweetening, flavoring or coloring agents mayalso be added.

In one embodiment, formulations of the present invention may beadministered in conjunction with one or more other medications. Suchother medications may be administered or co-administered in forms anddosages as known in the art.

The term “co-administration” or “combination therapy” is used todescribe a therapy in which at least two compounds are used to treatschizophrenia or another neuropsychiatric disease or condition asdescribed herein at the same time. In an embodiment, at least twocompounds in effective amounts are used to treat schizophrenia oranother neuropsychiatric disease or condition at the same time. Inanother embodiment, at least two compounds, the combination of whichcomprises an effective amount, are used to treat schizophrenia oranother neuropsychiatric disease or condition as described herein at thesame time. In an embodiment, the result of treatment with the at leasttwo compounds may be additive of the treatment results obtained usingeach compound separately, either directly additive, or additive to adegree lesser than the results obtained with the two compoundsseparately. In an embodiment, the result of treatment with the at leasttwo compounds may be synergistic, to varying degrees. In an embodiment,the result of treatment with the at least two compounds may be less thanthe treatment results obtained using each compound separately. In anaspect, the result of treatment with a composition encompassed herein issuch that, for one compound, the result of treatment is less than thatobtained with the compound separately, while the results of treatmentwith respect to the other compounds in the composition are about thesame as the results of treatment obtained separately.

Although the term co-administration encompasses the administration oftwo active compounds to the patient at the same time, it is notnecessary that the compounds be administered to the patient at the sametime, although effective amounts of the individual compounds will bepresent in the patient at the same time.

In an embodiment, a compound set forth herein can be co-administeredwith one or more atypical antipsychotics. Examples of atypicalantipsychotics include, but are not limited to fluphenazine,risperidone, olanzapine, clozapine, quetiapine, ziprasidone,aripiprazole, seritindole, zotepine, and perospirone. Examples ofantidepressants useful in combination therapy as encompassed hereininclude, but are not limited to, fluoxetine, citalopram, escitalopram,venlafaxine, duloxetine, bupropion.

Synthesis of Compound (I)

Standard synthetic methods and procedures for the preparation of organicmolecules and functional group transformations and manipulations,including the use of protective groups, can be obtained from therelevant scientific literature or from standard reference textbooks inthe field. Although not limited to any one or several sources,recognized reference textbooks of organic synthesis include: Smith, M.B.; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) ed.; John Wiley & Sons: New York, 2001; andGreene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,3^(rd); John Wiley & Sons: New York, 1999.

A method for preparing Compound (I) is described in U.S. Pat. No.7,166,617, the entire contents of which is incorporated herein byreference.

Pharmaceutical Compositions of Form (A) of Compound (I)HCl-2H₂O

The disclosure also provides pharmaceutical compositions comprising form(A) of Compound (I)-HCl-2H₂O and one or more pharmaceutically acceptablediluents, excipients, or carriers.

A “pharmaceutical composition” is a formulation containing form (A) ofCompound (I)-HCl-2H₂O in a form suitable for administration to asubject. In one embodiment, the pharmaceutical composition is in bulk orin unit dosage form. The unit dosage form is any of a variety of forms,including, for example, a capsule, an IV bag, a tablet, a single pump onan aerosol inhaler or a vial. The quantity of active ingredient (e.g., aformulation of form (A) of Compound (I)-HCl-2H₂O) in a unit dose ofcomposition is an effective amount and is varied according to theparticular treatment involved. One skilled in the art will appreciatethat it is sometimes necessary to make routine variations to the dosagedepending on the age and condition of the patient. The dosage will alsodepend on the route of administration. A variety of routes arecontemplated, including oral, pulmonary, rectal, parenteral,transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal,inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal,and the like. Dosage forms for the topical or transdermal administrationof form (A) of Compound (I)-HCl-2H₂O include powders, sprays, ointments,pastes, creams, lotions, gels, solutions, patches and inhalants. In oneembodiment, form (A) of Compound (I)-HCl-2H₂O is mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers or propellants that are required.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, carriers, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A pharmaceutical composition of the disclosure is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical), andtransmucosal administration. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates, and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

The term “therapeutically effective amount”, as used herein, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician. In an aspect, thedisease or disorder to be treated is a neuropsychiatric disease ordisorder. In another aspect, the disease or condition to be treated isschizophrenia.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays or in animal models, usuallyrats, mice, rabbits, dogs, or pigs. The animal model may also be used todetermine the appropriate concentration range and route ofadministration. Such information can then be used to determine usefuldoses and routes for administration in humans. Therapeutic/prophylacticefficacy and toxicity may be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., ED₅₀ (thedose therapeutically effective in 50% of the population) and LD₅₀ (thedose lethal to 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index, and it can be expressed asthe ratio, LD₅₀/ED₅₀. Pharmaceutical compositions that exhibit largetherapeutic indices are preferred. The dosage may vary within this rangedepending upon the dosage form employed, sensitivity of the patient, andthe route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active ingredient or to maintain the desired effect. Factors whichmay be taken into account include the severity of the disease state,general health of the subject, age, weight, and gender of the subject,diet, time and frequency of administration, drug combination(s),reaction sensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The pharmaceutical compositions containing form (A) of Compound(I)-HCl-2H₂O may be manufactured in a manner that is generally known,e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Pharmaceutical compositions may be formulated ina conventional manner using one or more pharmaceutically acceptablecarriers comprising excipients and/or auxiliaries that facilitateprocessing of the active ingredient into preparations that can be usedpharmaceutically. Of course, the appropriate formulation is dependentupon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating form (A)of Compound (I)-HCl-2H₂O in the required amount in an appropriatesolvent with one or a combination of ingredients enumerated above, asrequired, followed by filtered sterilization. Generally, dispersions areprepared by incorporating form (A) of Compound (I)-HCl-2H₂O into asterile vehicle that contains a basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, methods ofpreparation are vacuum drying and freeze-drying that yields a powder ofform (A) of Compound (I)-HCl-2H₂O plus any additional desired ingredientfrom a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, form (A) of Compound (I)-HCl-2H₂O can be incorporatedwith excipients and used in the form of tablets, troches, or capsules.Oral compositions can also be prepared using a fluid carrier for use asa mouthwash, wherein form (A) of Compound (I)-HCl-2H₂O in the fluidcarrier is applied orally and swished and expectorated or swallowed.Pharmaceutically compatible binding agents, and/or adjuvant materialscan be included as part of the composition. The tablets, pills,capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, form (A) of Compound (I)-HCl-2H₂O isdelivered in the form of an aerosol spray from pressured container ordispenser, which contains a suitable propellant, e.g., a gas such ascarbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives.

Transmucosal administration can be accomplished through the use of nasalsprays or suppositories. For transdermal administration, form (A) ofCompound (I)-HCl-2H₂O is formulated into ointments, salves, gels, orcreams as generally known in the art.

Form (A) of Compound (I)-HCl-2H₂O can be prepared with pharmaceuticallyacceptable carriers that will protect the compound against rapidelimination from the body, such as a controlled release formulation,including implants and microencapsulated delivery systems.

Biodegradable, biocompatible polymers can be used, such as ethylenevinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Methods for preparation of suchformulations will be apparent to those skilled in the art. The materialscan also be obtained commercially from Alza Corporation and NovaPharmaceuticals, Inc. Liposomal suspensions (including liposomestargeted to infected cells with monoclonal antibodies to viral antigens)can also be used as pharmaceutically acceptable carriers. These can beprepared according to methods known to those skilled in the art, forexample, as described in U.S. Pat. No. 4,522,811 (the contents of whichare incorporated herein in their entirety).

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the disclosure are dictated by and directlydependent on the unique characteristics of form (A) of Compound(I)-HCl-2H₂O and the particular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceuticalcompositions used in accordance with the application vary depending onthe agent, the age, weight, and clinical condition of the recipientpatient, and the experience and judgment of the clinician orpractitioner administering the therapy, among other factors affectingthe selected dosage. Dosages can range from about 0.01 mg/kg per day toabout 5000 mg/kg per day. In an aspect, dosages can range from about 1mg/kg per day to about 1000 mg/kg per day. In an aspect, the dose willbe in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/dayto about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg toabout 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, orcontinuous doses (which dose may be adjusted for the patient's weight inkg, body surface area in m², and age in years). In other aspects,dosages can range from about 16 mg of Compound (I) per day to about 64mg of Compound (I) per day administered in a single dose. In anotheraspect, dosages can range from about 30 mg of Compound (I) per day toabout 50 mg of Compound (I) per day administered in a single dose. In anaspect, the dosage of Compound (I) in the pharmaceutical composition is30 mg per day, 31 mg per day, 32 mg per day, 33 mg per day, 34 mg perday, 35 mg per day, 36 mg per day, 37 mg per day, 38 mg per day, 39 mgper day, 40 mg per day, 41 mg per day, 42 mg per day, 43 mg per day, 44mg per day, 45 mg per day, 46 mg per day, 47 mg per day, 48 mg per day,49 mg per day, and 50 mg per day administered in a single dose. In oneembodiment, the dosage of Compound (I) in the pharmaceutical compositionis 40 mg per day administered as a single dose.

An effective amount of a pharmaceutical agent is that which provides anobjectively identifiable improvement as noted by the clinician or otherqualified observer. As used herein, the term “dosage effective manner”refers to amount of form (A) of Compound (I)-HCl-2H₂O to produce thedesired effect in a subject.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

The pharmaceutical composition of the disclosure, are administeredorally, nasally, transdermally, pulmonary, inhalationally, buccally,sublingually, intraperintoneally, subcutaneously, intramuscularly,intravenously, rectally, intrapleurally, intrathecally and parenterally.In one embodiment, form (A) of Compound (I)-HCl-2H₂O is administeredorally. One skilled in the art will recognize the advantages of certainroutes of administration.

The dosage regimen utilizing form (A) of Compound (I)-HCl-2H₂O isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Techniques for formulation and administration of the disclosed compoundsof the application can be found in Remington: the Science and Practiceof Pharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa. (1995).In an embodiment, form (A) of Compound (I)-HCl-2H₂O is used inpharmaceutical preparations in combination with a pharmaceuticallyacceptable carrier or diluent. Suitable pharmaceutically acceptablecarriers include inert solid fillers or diluents and sterile aqueous ororganic solutions. Form (A) of Compound (I)-HCl-2H₂O will be present insuch pharmaceutical compositions in amounts sufficient to provide thedesired dosage amount in the range described herein.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Methods of Treatment

The disclosure also provides methods of treating a neuropsychiatricdisease or disorder in a subject in need thereof by administering to asubject in need of such treatment, a therapeutically effective amount ofform (A) of Compound (I)-HCl-2H₂O, or a pharmaceutical compositionthereof. The neuropsychiatric disease or disorder can be schizophrenia.

The term “subject” refers to any animal, including mammals, such as, butnot limited to, humans, mice, rats, other rodents, rabbits, dogs, cats,pigs, cattle, sheep, horses, or primates. Subjects may or may not havebeen diagnosed with Schizophrenia. Subjects may present one or moresigns or symptoms of schizophrenia.

In certain embodiments, subjects of the disclosure may have been treatedfor schizophrenia with one or more typical or atypical anti-psychotictherapies prior to, in combination with, or following treatment with apharmaceutical composition comprising form (A) of Compound (I). Incertain embodiments, subjects of the disclosure may have been treatedfor schizophrenia with one or more typical or atypical anti-psychotictherapies prior to treatment with a pharmaceutical compositioncomprising form (A) of Compound (I) and the one or more typical oratypical anti-psychotic therapies may have been ineffective to treat asign or symptom of schizophrenia in the subject.

Other features and advantages of the disclosure are apparent from thedifferent examples. The provided examples illustrate differentcomponents and methodology useful in practicing the disclosure.

The examples do not limit the claimed compositions, methods, and kits ofthe disclosure. Based on the present disclosure the skilled artisan canidentify and employ other components and methodology useful forpracticing the disclosure.

EXAMPLES Example 1

Increases in QTc interval were observed and seemed to be related to theexposure to Compound (I) and its metabolite BFB-520. QT prolongation wasparticularly obvious in a patient who was CYP2D6 poor metabolizer andwho showed high plasmatic levels of BFB-520. A further analysis of therelationship between QT/QTc and Compound (I) and BFB-520 concentrationswas performed. It was determined that to avoid QT prolongation, Cmax ofCompound (I) and BFB-520 should not exceed 80 ng/mL and 12 ng/mLrespectively.

In order to further evaluate the incidence of QT/QTc changes frombaseline greater than 30 and 60 ms and the incidence of QTc valuesgreater than 450, 480 and 500 ms, the following study was conducted.

Part 1 of this study was designed to characterize and compare thepharmacokinetic (PK) profile of Compound (I) when administered as MRformulations, and food effects, following a single dose administrationin a 6-way, within subject, crossover design.

Part 2 of the study was designed to evaluate the effect of multipledoses of the MR formulation chosen on safety, tolerability andcardiovascular parameters. Effects of Compound (I) on sleep parameterswill be also evaluated. In the CYR-101C01 study, Compound (I) had aneffect on slow wave sleep (SWS) distribution: Compound (I) significantlyincreased SWS in the first third of the night and decreased it in thelast third of the night. Results also suggested that Compound (I) couldhave sleep promoting effects since it improved sleep initiationparameters (sleep onset latency, latency to persistent sleep). In thecurrent study, sleep will be used as a biomarker that could help indefining the minimal active dose to be assessed in the next patientstudy. Sleep parameters will be analyzed by mean of VWatch methodology.

The formulations used in Part 1 of the study were selected from a designspace with active treatment, Compound (I) and HPMC a release controllingagent as the 2 main compositional variables. On the release rate axis ofthe design space, MR formulations will be described as slow (releaserate of 16-19 hours), medium (release rate of 10-12 hours) or fast(release rate of 5-7 hours). The 2-dimensional compositional formulationdesign space is shown in Scheme 1, where F1 to F4 represent the boundaryformulations.

Part 2 of the study was designed to assess the multiple doseadministration of the selected formulation from Part 1 at a low and highdose level compared with placebo in a larger naïve cohort of subjects.

Pharmacologic Profile (Nonclinical Studies):

In in vitro receptor binding studies, Compound (I) demonstrated a uniquebinding profile. Compound (I) bound with high affinity only to 5-HT2A,al-adrenergic and sigma2 receptors (K_(i)=7.53, 14.43, 8.19 nmol/L,respectively). The affinity for DA receptors was fairly weak (IC₅₀>1000nmol/L). Both main metabolites BFB-520 and BFB-999 showed a similarprofile as Compound (I), with lower affinity for σ2 receptors, and lowerand equal affinity to that of Compound (I) for 5-HT2A receptors,respectively.

In in vivo functional tests, Compound (I) acted as an antagonist atsigma2 and 5-HT2A receptors. Following oral administration, Compound (I)slightly increased dopamine turnover in the accumbens and striatum andincreased the output of DA metabolites such as DOPAC and HVA inprefrontal cortex at high dose levels. At effective dose levels inanimal models of antipsychotic activity, Compound (I) did not affectmonoamine levels, whereas, other antipsychotics markedly increased DAturnover and the output of DOPAC and HVA, reflecting their potent D2antagonistic effects.

Compound (I) was tested in male Wistar rats in several behavioralparadigms designed to evaluate the potential for producing antipsychoticactivity of drugs in humans. Compound (I) inhibited methamphetamine-,apomorphine-, and phencyclidine-induced hyperlocomotion in a similarmanner to other antipsychotics. Likewise, BFB-520 and BFB-999 alsoinhibited methamphetamine-induced hyperlocomotion with an ED50 higherthan that of Compound (I). Furthermore, Compound (I) significantlyameliorated PCP-induced social interaction impairment after repeatedadministration, whereas, other atypical antipsychotics did notameliorate this impairment, and improved impairment of spontaneousalternation behavior induced by MK-801.

Safety Pharmacology:

In a series of safety pharmacology studies, the effects of Compound (I)on general activity and behavior, the CNS, respiratory function,gastrointestinal system, and water and electrolyte excretion wereexamined in rats at an oral dose range of 1 to 30 mg/kg Compound (I)induced various changes in general activity and behavior. These clinicalsigns were observed between 0.25 to 4 hours post-dosing and disappearedby 6 hours post-dosing. Compound (I) inhibited CNS function anddecreased thresholds for electroshock-induced convulsion. High doses(>10 mg/kg) of Compound (I) affected respiratory function, inhibitedgastric emptying, damaged the gastrointestinal membrane, decreased urinevolume, and increased urine potassium excretion.

The effects of Compound (I) on the cardiovascular system were examinedin in vitro and in vivo studies. In in vitro electrophysiologicalstudies using guinea pig papillary muscle, Compound (I) at 1 μM or moreprolonged the action potential duration (APD) and at the same degree asrisperidone and haloperidol. Likewise, BFB-520 at 0.1 μM or more andBFB-999 at 1 μM or more prolonged the APD in isolated guinea pigpapillary muscles with the same or stronger degree than Compound (I). Inin vitro electrophysiological studies using cultured cells expressingcloned cardiac ion channels, Compound (I) inhibited IKr current with anIC50 of 0.325 μM, comparable to that of risperidone (0.319 μM). As forBFB-520, it blocked IKr current with an IC50 of 0.181 μM lower than thatof the parent compound but higher than those of haloperidol (0.026 μM),thioridazine (0.145 μM) or ziprasidone (0.134 μM).

Pharmacokinetic Profile:

Pharmacokinetic (PK) studies of Compound (I) have been performedparticularly in rats and monkeys. Following a single oraladministration, Compound (I) was rapidly absorbed. Plasma radioactivitypeaked between 0.63 and 2.75 hours in male rats, and between 3 and 3.5hours in male monkeys. The oral absorption rates were 90.3 to 94.7% inrats and 70.0 to 99.9% in monkeys. The elimination half-lives ofradioactivity from plasma were 45.13 to 51.52 hours in rats and 174.74to 184.78 hours in monkeys. The elimination half-lives of unchangedCompound (I) were 1.68 to 2.06 hours in rats, and 1.68 to 2.57 hours inmonkeys. The absolute oral bioavailability of Compound (I) was 52.4 to64.5% in rats and 90% or higher in monkeys.

During repeated administration of 1 mg/kg/day for 14 days to male rats,plasma radioactivity increased with increasing number of doses, reachingsteady-state after the 7^(th) administration. Food and gender effectswere also assessed in rats. When Compound (I) was administered orally tonon-fasted rats at 1 mg/kg, plasma radioactivity has a delayed T_(max)by about 1 h and a decreased C_(max) to about 72% of the value in fastedmale rats, though AUCs were similar in the two groups. Moreoverpharmacokinetic parameters for total radioactivity in female rats werecomparable to those in male rats. When ¹⁴C-Compound (I) was orallyadministered to lactating rats, it was considered that Compound (I)and/or its metabolites rapidly transferred into milk and were slowlyeliminated.

Compound (I) absorption was also studied in single and repeated dosetoxicity studies in rats and monkeys for toxicokinetics and, ingenotoxicity and embryofetal development studies for plasma exposureevidence. After single and repeated administration, exposure levels ofCompound (I) and its main metabolites BFB-520 and BFB-999 increased in adose-dependent manner in both rats and monkeys, with gender differencein rats only.

After single administration of BFB-520 in monkeys, exposure levels ofBFB-520, Compound (I) and BFB-999 increased with a dose increment largerthan the proportionate one. BFB-520 reached its maximum concentrationwithin 4 hours post-dosing, and T_(max) for Compound (I) and BFB-999were comparable to that of BFB-520. Finally, the brain transfer ofCompound (I) was studied with male rats after oral administration (10mg/kg). The C_(max) of plasma and brain concentrations were 3164.62ng/mL and 4946.62 ng/g, respectively. The K_(p) value (brain/plasmaconcentration ratio) was 1.38 mL/g.

Several metabolites (i.e. BFB-999, BFB-520 and BFB-885) were detected inplasma and urine of male and female rats and male monkeys after oraladministration of 14CCompound (I). The metabolic rate in female rats wasslower than that in male rats, but the metabolic profiles were similarbetween male and female rats. Even if Compound (I) was shown to bemetabolized in BFB-520 and BFB-999 by cytochromes P450 CYP1A2, CYP2C19,CYP2D6 and CYP3A4, further studies using human liver microsomes suggestthat Compound (I) is mainly metabolized by enzymatic reaction other thanCYP isoforms. As for BFB-520, it was metabolized by CYP2D6 and CYP3A4.No remarkable inhibitory effects on human P450 isoforms (CYP1A2, 2A6,2B6, 2C8/9, 2C19, 2E1 and 3A4) were observed, while a weak inhibitoryeffect was shown on CYP2D6. Investigation of the drug-drug interactionof Compound (I) on in vitro metabolism determined IC₅₀ value more than50 μM for the following concomitant drugs: ketoconazole, fluvoxamine,paroxetine, and lorazepam.

The major route of elimination of radioactivity in rats and monkeysfollowing a single oral or intravenous administration was via the feces.The excretion to bile was 44.2% within 48 hours after a single oraladministration to bile duct cannulated rats. Urinary excretion rates ofradioactivity were about 35% in rats and monkeys. Total recovery ofgiven radioactivity was 101.1% (including the carcass) for rats and92.6% for monkeys within 168 hours after a single oral administration.After repeated administration to rats for 14 days, the total recovery ofgiven radioactivity was 96.6% in urine and feces, and 0.7% in carcasswithin 168 hours after the last administration. The enterohepaticcirculation rate was determined to be about 27% after intraduodenaladministration of bile samples from ¹⁴C-Compound (I)—treated rats.

In an embodiment, the compositions may be formulated in a conventionalmanner using one or more pharmaceutically acceptable carriers and mayalso be administered in controlled-release formulations.

Example 2

Part 1 of the study is an open-label, non-randomized, single dose,6-period crossover design in 12 healthy CYP 2D6 EM male subjects. ForPart 1, subjects will receive the following regimens in a non-randomisedmanner:

Regimen A: MR Formulation prototype 1: 32 mg Compound (I) slow releaseadministered in the fasted state

Regimen B: MR Formulation prototype 2 administered in the fasted state

Regimen C: MR Formulation prototype 3 administered in the fasted stateor formulation prototype 1 or 2 administered in the fed state

Regimen D: MR Formulation prototype 4 administered in the fasted stateor formulation prototype 1, 2 or 3 administered in the fed state

Regimen E: MR Formulation prototype 5 administered in the fasted stateor formulation prototype 1, 2, 3 or 4 administered in the fed state

Regimen F: MR Formulation prototype 1, 2, 3, 4 or 5 administered in fedstate.

Formulation selection within Part 1 are made after a complete review ofall data collected from the previous regimen and the formulation, dosesand requirement for the optional return visit for Part 2 are made aftera complete review of all data from Part 1.

Part 2 of the study is a double-blind, randomized, placebo-controlled,6-sequence, 3-period crossover design in 24 healthy CYP 2D6 EM male andfemale subjects. For Part 2, on each of the 3 study periods, subjectsreceive the following regimes in a randomized manner:

Regimen G: Placebo QD for 7 days

Regimen H: High dose MR formulation prototype QD for 7 days

Regimen I: Low dose MR formulation prototype QD for 7 days

Based on the above concept of design space, the IMP formulations used inPart 1 of the study are selected from a design space with activetreatment Compound (I) and Hypromellose (HPMC) as the releasecontrolling agent (the release controlled by the HPMC viscosity based onthe ratio of 2 HPMC polymers) as the two main compositional variables.The 2-dimensional compositional formulation design space is shown inTable 1, where F1 to F4 represent the boundary formulations. Part 2 ofthe study is designed to assess the multiple dose administration of theselected formulation from Part 1 at a low and high dose level comparedwith placebo in a larger naïve cohort of subjects.

TABLE 1 Excipient Quantitative Composition Range for Design Space 16 mgSlow 64 mg Slow 16 mg Fast 64 mg Fast Formulation 1 Formulation 2Formulation 3 Formulation 4 Component % w/w % w/w % w/w % w/w Compound(I)* 6.40 25.60 6.40 25.60 Hypromellose 12.00 6.00 36.00 30.00 K100LV CRHypromellose 24.00 24.00 — — K4M CR Microcrystalline 36.10 22.90 36.1022.90 Cellulose PH102** Lactose Fastflo 20.00 20.00 20.00 20.00 316Silica Colloidal 0.50 0.50 0.50 0.50 Anhydrous, Aerosil 200 PharmaMagnesium 1.00 1.00 1.00 1.00 stearate Total 100.00 100.00 100.00 100.00*Salt correction factor of 1.2 applied. **The amount of MicrocrystallineCellulose PH102 will be adjusted accordingly to maintain the same tabletweight.

Under the composition details we therefore present the extremes of doserange of 16-64 mg Compound (I) and ranges for levels of HypromelloseK100LV CR and Hypromellose K4M CR in the MR tablet, with theunderstanding that any interim formulation within these ranges could bemanufactured and dosed as an IMP during the clinical study. All othercomponents of the formulations remain constant with the exception ofMicrocrystalline Cellulose PH102 which may be adjusted to maintaintablet weight based on the potency and purity of the drug substance andweights for Hypromellose K100LV CR and Hypromellose K4M CR. The finalcomposition of the selected formulations is recorded in batch recordsproduced for clinical trial manufactures.

Composition of Compound (I) Prototype MR Tablet (Formulations 1, 2, 3,and 4)

The complete statement of the components and quantitative composition ofCompound (I) Prototype MR Tablet Formulations 1, 2, 3, and 4 is given inTable 2. In line with the formulation design space approach described inSection 2.1.P.1, this formulation represents the extremes of dose rangeof 16-64 mg Compound (I) and ranges in concentrations of HypromelloseK100LV CR and Hyromellose K4M CR that could be used in the study.

TABLE 2 Composition of Compound (I) Prototype MR Tablet (Formulations 1,2, 3 and 4) 16 mg Slow 64 mg Slow 16 mg Fast 64 mg Fast Formulation 1Formulation 2 Formulation 3 Formulation 4 Ref. to Component mg/tabletmg/tablet mg/tablet mg/tablet Function Standard Compound (I)¹ 19.2076.80 19.20 76.80 Active DS Section or other as appropriate Hypromellose36.00 18.00 108.00 90.00 Release USP, Ph. K100LV CR Modifier Eur., JPHypromellose 72.00 72.00 — — Release USP, Ph. K4M CR Modifier Eur., JPMicrocrystalline 108.30 68.70 108.30 68.70 Filler Ph. Eur., CelluloseNF, JP PH102² Lactose Fastflo 60.00 60.00 60.00 60.00 Filler NF/USP, 316Ph. Eur., JP Silica Colloidal 1.50 1.50 1.50 1.50 Glidant USP, Ph.Anhydrous, Eur., JP Aerosil 200 Pharma Magnesium 3.00 3.00 3.00 3.00Lubricant Ph. Eur., stearate NF, JP Total weight 300.00 300.00 300.00300.00 ¹Salt correction factor of 1.2 applied ²The amount ofMicrocrystalline Cellulose PH102 will be adjusted accordingly tomaintain the same tablet weight.

Table 3 shows the batch formulae for Compound (I) Prototype MR TabletFormulations 1, 2, 3 and 4. These formulations represent the extremes ofthe dose range of Compound (I) and concentrations of Hypromellose K100LVCR and Hypromellose K4M CR that could be used in the study. Thecompositional ratio of Silica Colloidal Anhydrous, Lactose Fastflo 316and Magnesium Stearate will remain constant. The compositional ratio ofMicrocrystalline Cellulose PH102 may be adjusted based on the potencyand purity of the drug substance and the weights for Hypromellose K100LVCR and Hypromellose K4M CR to maintain tablet weight of 300 mg.

TABLE 3 “Design Space” Batch Formulae for Compound (I) Prototype MRTablet 16 mg Slow 64 mg Slow 16 mg Fast 64 mg Fast Formulation 1Formulation 2 Formulation 3 Formulation 4 Component % w/w % w/w % w/w %w/w Compound (I)¹ 6.40 25.60 6.40 25.60 Hypromellose 12.00 6.00 36.0030.00 K100LV CR Hypromellose 24.00 24.00 — — K4M CR Microcrystalline36.10 22.90 36.10 22.90 Cellulose PH102² Lactose Fastflo 20.00 20.0020.00 20.00 316 Silica Colloidal 0.50 0.50 0.50 0.50 Anhydrous, Aerosil200 Pharma Magnesium 1.00 1.00 1.00 1.00 stearate Total 100.00 100.00100.00 100.00 ¹Salt correction factor of 1.2 applied. ²The amount ofMicrocrystalline Cellulose PH102 will be adjusted accordingly tomaintain the same tablet weight.

Scheme 2: Manufacture of Compound (I) Prototype MR Tablet ComponentProcess Control Compound (I) Weigh the required Quantity of Compound (I)Hypromellose K100LV quantity of Compound (I), Quantity of HypromelloseCR Hypromellose K100LV K100LV CR Hypromellose K4M CR CR, HypromelloseK4M Quantity of Hypromellose (if required) CR (if required), K4M CR (ifrequired) Microcrystalline Cellulose Microcrystalline Cellulose Quantityof PH102 PH102, Lactose Fastflo Microcrystalline Cellulose LactoseFastflo 316 316 and Silica Colloidal PH102 Silica Colloidal Anhydrousand screen Quantity of Lactose Anhydrous, Aerosil 200 through a suitablysized Fastflo 316 Pharma sieve. Transfer into a Quantity of Silicasuitably sized container Colloidal Anhydrous, and mix. Aerosil 200Pharma Screen the entire blend Mesh size of sieve screen through asuitably sized Mixing Time and Speed sieve. Transfer into the originalsuitably sized container and mix. ↓ Magnesium stearate Weigh therequired Quantity of Magnesium quantity of Magnesium Stearate Stearateand screen Mesh size of sieve screen through a suitably sized MixingTime and Speed sieve. Transfer to the container above and mix This isthe Compound (I) Prototype MR Tablet Blend ↓ Compound (I) PrototypeCompress the Compound Quantity of Compound (I) MR Tablet Blend (I)Prototype MR Tablet Prototype MR Tablet Blend into tablets Blend This isthe Compound (I) ¹Tablet appearance Prototype MR Tablet. ²Compressionforce ↓ ³Tablet Hardness ⁴Tablet weight Package the Compound (I)Prototype MR Tablet in container closure. ¹Tablet appearance will beassessed as an in process control during batch manufacture, the detailsof which will be recorded in the batch manufacturing record ²Compressionforce will be used throughout the manufacturing process and this may beadjusted to ensure that the correct tablet hardness is achieved. ³Tablethardness will be measured periodically throughout batch manufacture asdefined in the batch manufacturing record. ⁴Tablet weight will bemeasured as an in process control during batch manufacture, the detailsof which will be recorded in the batch manufacturing record.

The amount of Compound (I) and each excipient is controlled by weightusing a suitably calibrated balance to confirm that the correctformulation composition is achieved. A second operator verifies theweight. Blend uniformity is controlled by the pre-defined mixingconditions detailed in Scheme 2. These parameters have been developed toensure homogeneity of all potential formulation blends within theproposed design space. Execution of these processing instructions willbe controlled and documented within the batch manufacturing record. Toensure that content uniformity is uniform throughout the design space,development batches at the points in the design space described inScheme 1 have been manufactured and tested. Uniformity of content of thefinal tablet is assessed by assay.

Tablet hardness is controlled by application of a consistent pressurewith regular testing (destructive) throughout the batch using the TabletCompression Hardness Test.

The tablets are pressed manually; each tablet is weighed separatelyusing a suitably calibrated balance and a second operator verifies theweight.

All excipients used in the formulations comply with the currentmonographs of the Ph. Eur., the USP/NF or JP requirements as indicatedbelow. All excipients are purchased from approved suppliers.Manufacturer's Certificate of Analysis will be accepted and allexcipients received at Quotient Clinical Ltd will undergo identificationtests as appropriate according to Quotient Clinical Ltd receiptrequirements.

TABLE 4 Specification for Compound (I) Prototype MR Tablet Test MethodAcceptance Criteria Appearance Visual Off-white tablets with mottledbeige speckles, free from visual defects Assay HPLC 90.0%-110.0% ofnominal Identity HPLC Retention time of test sample conforms with theretention time of reference standard ±3% Related Substances HPLC Report≥ 0.1% Impurity A ≤ 1.0% 2-isomer ≤ 1.0% Unspecified Impurities NMT 0.5%Total Impurities NMT 3.0% Content Uniformity HPLC AV ≤ 15.0 DissolutionHPLC Report results

Dissolution Test

The dissolution test is a pharmacopoeial method conducted according toUSP monograph <711>apparatus 2. The dissolution medium is 450 mL 0.01Mhydrochloric acid with a pH switch with double strength Fasted StateSimulated Intestinal Fluid (version 2) giving a total volume of 900 mLand agitation at 75 rpm.

Samples are analyzed for Compound (I) content by a reverse phaseisocratic HPLC method using an Intersil ODS-3V (4.6 mm×150 mm) 5 mcolumn or suitably validated alternative with UV detection at 248 nm.Mobile phase is comprised of Acetonitrile: Water: Trifluroacetic acid.

Description of HPLC Assay, Identity and Content Uniformity method forCompound (I) Prototype MR Tablets

The method for assay of the active ingredient content of the Compound(I) Prototype MR Tablet is a reverse phase isocratic HPLC method usingan Intersil ODS-3V (4.6 mm×150 mm) 5 m column or suitably validatedalternative with UV detection at 248 nm.

Mobile phase is comprised of Acetonitrile: Water: Trifluroacetic acid.

Description of Related Substances Test

The method for related substances of the Compound (I) Prototype MRTablet is a reverse phase gradient HPLC method using an Intersil ODS-3V(4.6 mm×150 mm) 5 m column or suitably validated alternative with UVdetection at 248 nm. Mobile phase A is comprised of 0.1% TFA in Water,mobile phase B is 0.1% TFA in Acetonitrile.

Compound (I) C02: Once a Day Formulation

A Two-Part Study Designed to Evaluate the Pharmacokinetic Profile ofCompound (I) and its Main Metabolites Following Single and Multiple DoseModified Release Prototype Formulation Administration in Healthy CYP2D6Extensive Metabolizer Male and Female Subjects, and to Evaluate theRelationship Between the Pharmacokinetic Profile of Compound (I) and itsMain Metabolites and Cardiovascular Parameters. The study designs forpart 1 and part 2 are shown in FIGS. 7 and 8 , respectively, and FIG. 9shows the period scheme for dosing.

TABLE 5 Summary of Select PK Parameters - Period 1 (32 mg Slow Release,Fasted) Tmax Cmax Tlag t½ AUClast (h) (ng/mL) (h) (h) (h*ng/mL) MIN-101N 10 10 10 9 10 Mean NA 22.52 NA 6.257 211.9 Median    2.25 23.74  05.353 220.4 CV % NA 28.3 NA 38.1 18.6 BFB-520 N 10 10 10 4 10 Mean NA1.321 NA 6.540 18.6 Median  4 1.294   0.5 6.458 18.04 CV % NA 27.7 NA21.1 24.7 BFB-999 N 10 10 10 5 10 Mean NA 1.510 NA 6.202 16.02 Median  31.436    0.25 5.486 15.22 CV % NA 19.5 NA 27.3 22.3

In addition, the plasma concentration-time profiles for Compound (I),BFB-520, and BFB-999 are shown in FIGS. 1-3 . The C_(max) for Compound(I), BFB-520, and BFB-999 is shown in FIG. 4 . Effects on QTcF byCompound (I), BFB-520, and BFB-999 is shown in FIG. 5 .

MR Formulation under Fasted Conditions:

-   -   Short lag time suggestive of fast bioavailability    -   Exposure variability is generally low    -   Low to non-quantifiable values for most by Hour 24    -   PK is generally dose proportional for Compound (I) & BFB-999,        and less so for BFB-520    -   Inversion of BFB-520 & BFB-999 occurred with generally        suppressed levels of BFB-520, and a higher BFB-999 to BFB-520        ratio    -   MR formulation findings suggest shorter time in small intestine        is helpful in suppressing BFB-520 levels    -   Half-life for Compound (I) and 2 metabolite in 3-8 hour range,        longer for 40 mg slow release most likely due to flip-flop        (absorption & elimination balanced during terminal phase)    -   Simulation results indicate steady state within 10-14 days, and        no accumulation for all 3 analytes.

Food Effect:

-   -   Positive food effect evident—Higher exposure    -   MR formulation behaved similar to IR formulation with rapid        release and absorption, mostly prior to reaching colon    -   This explains further increase in BFB-520 levels    -   Due to rapid absorption Compound (I) Cmax increase was ˜2×,        BFB-520 Cmax increase was ˜3×, and BFB-999 Cmax increase was        ˜0.5×    -   Half-life was shortened substantially: Fed to Fasted ratios were        -   0.5 for Compound (I)        -   0.8 for BFB-520        -   0.6 for BFB-999    -   Consequently, accumulation is not expected    -   AUC increase was minimal (compared to C_(max)): 1.3 to 1.8        multiples with highest increase to BFB-520 Compound (I) C03        Phase IIB in patients with schizophrenia

A Phase IIb, Multi-centre, Randomized, Double-blind, Parallel-group,Placebo-controlled Study to Evaluate the Efficacy, Tolerability andSafety of Compound (I) in Patients with Negative Symptoms ofSchizophrenia Followed by a 24-week, Open-label extension. The studydesign is shown in FIG. 10 .

Study Objectives:

Primary: To evaluate the efficacy of Compound (I) compared to placebo inimproving the negative symptoms of schizophrenia as measured by thechange from Baseline in the Positive and Negative Syndrome Scale (PANSS)negative subscale score of the pentagonal model over 12 weeks oftreatment.

Main Secondary:

-   -   To evaluate the efficacy of Compound (I) compared to placebo in        improving other symptoms of schizophrenia as measured by the        change from baseline in the PANSS total score, and sub-scores of        the pentagonal model AND 3 factors analysis over 12 weeks of        double blind treatment.    -   To evaluate the efficacy of Compound (I) compared to placebo in        improving negative symptoms of schizophrenia as measured by the        change from Baseline in the Brief Negative Symptoms Scale (BNSS)        total score over 12 weeks of double blind treatment.    -   To assess the effects versus placebo of Compound (I) on        cognitive function as measured by the Brief Assessment of        Cognition in Schizophrenia (BACS) battery over 12 weeks of        double blind treatment.    -   To assess the persistence of efficacy, and the safety and        tolerability of Compound (I) during the 24-week, of open-label        extension phase.

Other Objectives:

-   -   To evaluate the effects versus placebo of Compound (I) on        depressive symptoms as measured by the Calgary Depression Scale        for Schizophrenia (CDSS) over 12 weeks of double blind        treatment.    -   To evaluate the effects versus placebo of Compound (I) on social        functioning by means of the Personal and Social Performance        (PSP) over 12 weeks of double blind treatment.    -   To assess the effects versus placebo of Compound (I) on sleep        architecture and continuity as measured with the help of the        V-Watch methodology over 12 weeks of double blind treatment.

Main Inclusion Criteria:

-   -   Male or female patient, 18 to 60 years of age, inclusive.    -   Patient meets the diagnostic criteria for schizophrenia as        defined in the Diagnostic and Statistical Manual of Mental        Disorders-Fifth Edition (DSM-V)    -   Patient being stable in terms of positive symptoms over the last        three months according to his treating psychiatrist    -   Patient presenting with negative symptoms over the last three        months according to his treating psychiatrist    -   Patient with PANSS negative sub-score of at least 20.    -   Patient with PANSS item score of <4 on: P4 Excitement,        hyperactivity P7 Hostility P6 Suspiciousness G8        Uncooperativeness G14 Poor impulse control    -   No change in psychotropic medication during the last month    -   Patient must be extensive metabolizers for P450 CYP2D6, as        determined by genotyping test before the first drug dose is        administered.

Main Exclusion Criteria:

-   -   Current bipolar disorder, panic disorder, obsessive compulsive        disorder, or evidence of mental retardation.    -   Patient's condition is due to direct physiological effects of a        substance (e.g., a drug of abuse, or medication) or a general        medical condition.    -   Significant risk of suicide or attempted suicide, or of danger        to self or others.    -   Patient who cannot be discontinued from psychotropics other than        those allowed.    -   Patient who received clozapine within 6 months of the Screening        visit.    -   Patient receiving treatment with depot antipsychotic medication        can be enrolled in the study 4 weeks after the last injection.    -   Patient with a history of significant other major or unstable        neurological, neurosurgical (e.g., head trauma), metabolic,        hepatic, renal, hematological, pulmonary, cardiovascular,        metabolic, gastrointestinal, or urological disorder.    -   Patient with a clinically significant electrocardiogram (ECG)        abnormality that could be a safety issue in the study, including        QT interval value corrected for heart rate using the        Fridericia's formula (QTcF) >430 msec for males and >450 msec        for females.

Main Efficacy Assessments:

-   -   Positive and Negative Symptoms Scale (PANSS)    -   Brief Negative Symptoms Scale (BNSS): semi structured interview,        designed to measure the current level of severity of negative        symptoms in schizophrenia and schizoaffective disorder        (Kirkpatrick et al.)        -   Anhedonia        -   Distress        -   Asociality        -   Avolition        -   Blunted affect        -   Alogia    -   Brief Assessment of Cognition in Schizophrenia (BACS)    -   Personal and Social Performance (PSP): assess social        functioning; clinician rated        -   socially useful activities,        -   personal and social relationships,        -   self-care        -   disturbing and aggressive behavior    -   Sleep architecture and continuity

Sleep Assessment:

-   -   Sleep and circadian rhythm disruptions are reported in 30% to        80% of patients with schizophrenia.    -   Patients with insomnia report        -   lower quality of life        -   greater symptom severity        -   worse adherence/compliance to treatment    -   Sleep disturbances have also been associated with enhanced        psychosis    -   Sleep is important for memory consolidation, thus disturbances        in sleep architecture, or circadian de-synchronization could        also contribute to the cognitive impairment observed in        schizophrenia.    -   Compound (I) showed effects on sleep architecture in the        previous Phase 2a study that could possibly be linked to the        improvements observed on negative symptoms and cognition, thus        they will be further investigated in the present study.        -   In a subgroup of patients (20) who underwent sleep            recordings (PSG), sleep was evaluated at Baseline and            Day 14. Compound (I) had an effect on            -   Slow Wave Sleep (SWS) distribution: it shifted SWS from                the end to the beginning of the night: Compound (I)                significantly increased SWS in the first third of the                night and decreased it in the last third of the night.            -   Sleep initiation parameters (sleep onset latency,                latency to persistent sleep).        -   Subjective sleep quality as measured by PSQI improved and            this improvement was greater with Compound (I) than with            placebo although not statistically significant.

V-Watch: A Sleep Biomarker & Companion Diagnostic Tool

VWatch methodology overview-1 (FIG. 6 ): Compared to the standardpolysomnography (PSG) which rely on the measure of brain waves, V-Watchmethodology uses physiological measures to assess sleep.

Physiological systems and their regulations are dependent of thephysiological state (waking or sleeping)

The sleeping process affects the whole body and not only the brain

-   -   Changes seen in cortical waves during sleep are only reflections        of transitions between sleep stages and they are not the only        method to assess these transitions    -   These transitions can also be detected from other physiological        systems

Heart rate characteristics (level, regularity, variability and suddenchanges) and body motor activity can be used to discriminate waking fromsleeping and to distinguish the main sleep stages.

Example 3. Various Tablet Formulations of Compound (I)

TABLE 6-1 Compositions for 16 mg and 64 mg MIN-101 MR tabletformulations 117055-01-1 117055-01-2 117055-01-3 117055-01-4 (16 mgSlow) (64 mg Slow) (16 mg Fast) (64 mg Fast) g/per g/per g/per g/per 50g 50 g 50 g 50 g Composition % w/w mg/tablet batch % w/w mg/tablet batch% w/w mg/tablet batch % w/w mg/tablet batch MIN-101* 5.33 16.0 2.6721.33 64.0 10.67 5.33 16.0 2.67 21.33 64.0 10.67 Hypromellose K4M 30.0090.0 15.00 30.00 90.0 15.00 — — — — — — CR Hypromellose — — — — — —30.00 90.0 15.00 30.00 90.0 15.00 K100LV CR Microcrystalline 62.67 188.031.34 46.67 140.0 23.34 62.67 188.0 31.34 46.67 140.0 23.34 CellulosePH102 Silica Colloidal 1.00 3.0 0.50 1.00 3.0 0.50 1.00 3.0 0.50 1.003.0 0.50 Anhydrous, Aerosil 200 Pharma Magnesium stearate 1.00 3.0 0.501.00 3.0 0.50 1.00 3.0 0.50 1.00 3.0 0.50 Total 100.00 300.0 50.01100.00 300.0 50.01 100.00 300.0 50.0 100.00 300.0 50.01 *Salt correctionfactor missed in error

TABLE 6-2 Compositions for 16 mg and 64 mg MIN-101 MR tabletformulations 117055-08-1 117055-08-2 117055-08-3 117055-08-4 (16 mgSlow) 64 mg Slow 16 mg Fast 64 mg Fast g/per g/per g/per g/per 50 g 50 g50 g 50 g Composition % w/w mg/tablet batch % w/w mg/tablet batch % w/wmg/tablet batch % w/w mg/tablet batch MIN-101* 5.33 16.0 2.67 21.33 64.010.67 5.33 16.0 2.67 21.33 64.0 10.67 Hypromellose 35.00 105.0 17.5035.00 105.0 17.50 — — — — — — K100LV CR Hypromellose E50 — — — — — —20.0 60.0 10.00 20.0 60.0 10.00 Microcrystalline 57.67 173.0 28.84 41.67125.0 20.84 72.67 218.0 36.34 56.67 170.0 28.34 Cellulose PH102 SilicaColloidal 1.00 3.0 0.50 1.00 3.0 0.50 1.00 3.0 0.50 1.00 3.0 0.50Anhydrous, Aerosil 200 Pharma Magnesium stearate 1.00 3.0 0.50 1.00 3.00.50 1.00 3.0 0.50 1.00 3.0 0.50 Total 100.00 300.0 50.01 100.00 300.050.01 100.00 300.0 50.0 100.00 300.0 50.01 *Salt correction factormissed in error

TABLE 7 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations117055-11-1 117055-11-2 117055-11-3 117055-11-4 (16 mg Slow) 64 mg Slow16 mg Fast 64 mg Fast g/per g/per g/per g/per 50 g 50 g 50 g 50 gComposition % w/w mg/tablet batch % w/w mg/tablet batch % w/w mg/tabletbatch % w/w mg/tablet batch MIN-101* 6.4 19.2 3.2 25.6 76.8 12.8 6.419.2 3.2 25.6 76.8 12.8 Hypromellose 35.0 105.0 17.5 35.0 105.0 17.5 — —— — — — K100LV CR Hypromellose E50 — — — — — — 20.0 60.0 10.0 20.0 60.010.0 Mannitol M200 56.6 169.3 28.3 37.4 112.2 18.7 71.6 214.8 35.8 52.4157.2 26.2 Silica Colloidal 1.0 3.0 0.5 1.0 3.0 0.5 1.0 3.0 0.5 1.0 3.00.5 Anhydrous, Aerosil 200 Pharma Magnesium stearate 1.0 3.0 0.5 1.0 3.00.5 1.0 3.0 0.5 1.0 3.0 0.5 Total 100.00 300.0 50.0 100.0 300.0 50.0100.0 300.0 50.0 100.0 300.0 50.0 *Salt correction factor of 1.2applied.

TABLE 8 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations117055-13-1 117055-13-2 117055-13-3 117055-13-4 117055-13-5 117055-13-616 mg Slow 64 mg Slow 64 mg Slow 64 mg Slow 16 mg Fast 64 mg Fast g/perg/per g/per g/per g/per g/per % mg/ 50 g % mg/ 50 g % mg/ 50 g % mg/ 50g % mg/ 50 g % mg/ 50 g Composition w/w tablet batch w/w tablet batchw/w tablet batch w/w tablet batch w/w tablet batch w/w tablet batchMIN-101* 6.4 19.2 3.20 25.6 76.8 12.80 25.6 76.8 12.8 25.6 76.8 12.8 8.419.2 3.2 25.6 76.8 12.8 Hypromellose 35.0 105.0 17.50 35.0 105.0 17.5050.0 150.0 25.0 — — — 20.0 60.0 10.0 20.0 60.0 10.0 K100LV CRHypromellose — — — — — — — — — 30.0 90.0 15.0 — — — — — — K4M MannitolM200 28.3 84.9 14.15 18.7 56.1 9.35 22.4 67.2 11.2 42.4 127.2 21.2 71.6214.8 35.8 52.4 157.2 26.2 Microcrystalline 28.3 84.9 14.15 18.7 56.19.35 — — — — — — — — — — — — Cellulose PH102 Silica Colloidal 1.0 3.00.50 1.0 3.0 0.50 1.0 3.0 0.5 1.0 3.0 0.5 1.0 3.0 0.5 1.0 3.0 0.5Anhydrous, Aerosil 200 Pharma Magnesium 1.0 3.0 0.50 1.0 3.0 0.50 1.03.0 0.5 1.0 3.0 0.5 1.0 3.0 0.5 1.0 3.0 0.5 stearate Total 100.0 300.050.00 100.0 300.0 50.00 100.0 300.0 50.0 100.0 300.0 50.0 100.0 300.050.0 100.0 300.0 50.0 *Salt correction factor of 1.2 applied.

TABLE 9 Compositions for 64 mg MIN-101 MR tablet formulations117055-17-1 117055-17-2 117055-17-3 117055-17-4 (64 mg Slow) (64 mgSlow) (64 mg Fast) (64 mg Fast) g/per g/per g/per g/per 50 g 50 g 50 g50 g Composition % w/w mg/tablet batch % w/w mg/tablet batch % w/wmg/tablet batch % w/w mg/tablet batch MIN-101* 25.60 76.80 12.80 25.676.8 12.80 25.60 76.80 12.80 25.60 76.80 12.80 Hypromellose 50.00 150.0025.00 50.0 150.0 25.00 20.00 60.00 10.00 20.00 60.00 10.00 K100LV CRMannitol M200 13.44 40.32 6.72 15.68 47.04 7.84 31.44 94.32 15.72 36.68110.04 18.34 Microcrystalline 8.96 26.88 4.48 6.72 20.16 3.36 20.9662.88 10.48 15.72 47.16 7.86 Cellulose PH102 Silica Colloidal 1.00 3.000.50 1.0 3.0 0.50 1.00 3.00 0.50 1.00 3.00 0.50 Anhydrous, Aerosil 200Pharma Magnesium stearate 1.00 3.00 0.50 1.0 3.0 0.50 1.00 3.00 0.501.00 3.00 0.50 Total 100.0 300.00 50.00 100.00 300.00 50.00 100.00300.00 50.0 100.00 300.00 50.0 *Salt correction factor of 1.2 applied.

TABLE 10 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations117055-21-1 117055-21-2 117055-21-3 64 mg Fast 64 mg Fast 16 mg Fastg/per g/per g/per mg/ 50 g mg/ 50 g mg/ 50 g Composition % w/w tabletbatch % w/w tablet batch % w/w tablet batch MIN-101* 25.60 76.80 12.8025.60 76.80 12.80 6.40 19.20 3.20 Hypromellose 25.00 75.00 12.50 25.0075.00 12.50 25.00 75.00 12.50 K100LV CR Mannitol M200 28.44 85.32 14.2233.18 99.54 16.59 46.62 139.86 23.31 Microcrystalline 18.96 56.88 9.4814.22 42.66 7.11 19.98 59.94 9.99 Cellulose PH102 Silica Colloidal 1.003.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 Anhydrous, Aerosil 200 PharmaMagnesium 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 stearate Total100.00 300.00 50.00 100.00 300.00 50.00 100.00 300.00 50.00 117055-24-1117055-24-2 117055-24-3 16 mg Slow 16 mg Slow 16 mg Slow g/per g/perg/per mg/ 50 g mg/ 50 g mg/ 50 g Composition % w/w tablet batch % w/wtablet batch % w/w tablet batch MIN-101* 6.40 19.20 3.20 6.40 19.20 3.206.40 19.20 3.20 Hypromellose 50.00 150.00 25.00 50.00 150.00 25.00 55.00165.00 27.50 K100LV CR Mannitol M200 24.96 74.88 12.48 29.12 87.36 14.5625.62 76.86 12.81 Microcrystalline 16.64 49.92 8.32 12.48 37.44 6.2410.98 32.94 5.49 Cellulose PH102 Silica Colloidal 1.00 3.00 0.50 1.003.00 0.50 1.00 3.00 0.50 Anhydrous, Aerosil 200 Pharma Magnesium 1.003.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 stearate Total 100.00 300.0050.00 100.00 300.00 50.00 100.00 300.00 50.00

TABLE 11 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations117055-26-1 117055-26-2 117055-26-3 117055-26-3 16 mg Slow 64 mg Slow 16mg Fast 64 mg Fast g/per g/per g/per g/per 50 g 50 g 50 g 50 gComposition % w/w mg/tablet batch % w/w mg/tablet batch % w/w mg/tabletbatch % w/w mg/tablet batch MIN-101* 6.40 19.20 3.20 25.6 76.80 12.806.40 19.20 3.20 25.60 76.80 12.80 Hypromellose 55.00 165.00 27.50 50.00150.00 25.00 27.00 81.00 13.50 22.00 66.00 11.00 K100LV CR Mannitol M20025.62 76.86 12.81 15.68 47.04 7.84 45.22 135.66 22.61 35.28 105.84 17.64Microcrystalline 10.98 32.94 5.49 6.72 20.16 3.36 19.38 58.04 9.69 15.1245.36 7.56 Cellulose PH102 Silica Colloidal 1.00 3.00 0.50 1.00 3.000.50 1.00 3.00 0.50 1.00 3.00 0.50 Anhydrous, Aerosil 200 PharmaMagnesium stearate 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 1.003.00 0.50 Total 100.00 300.00 50.00 100.00 300.00 50.00 100.00 300.0050.00 100.00 300.00 50.00 *Salt correction factor of 1.2 applied.

TABLE 12 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations117055-30-1 117055-30-2 117055-30-3 16 mg Fast 64 mg Fast 16 mg Fastg/per g/per g/per 50 g 50 g 50 g Composition % w/w mg/tablet batch % w/wmg/tablet batch % w/w mg/tablet batch MIN-101* 6.40 19.20 3.20 25.6076.80 12.80 6.40 19.20 3.20 Hypromellose 27.00 81.00 13.50 22.00 66.0011.00 30.00 90.00 15.00 K100LV CR Mannitol M200 45.22 135.66 22.61 35.28105.84 17.64 43.12 129.36 21.56 Microcrystalline 19.38 58.14 9.69 15.1245.36 7.56 18.48 55.44 9.24 Cellulose PH102 Silica Colloidal 1.00 3.000.50 1.00 3.00 0.50 1.00 3.00 0.50 Anhydrous, Aerosil 200 PharmaMagnesium 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 stearate Total100.00 300.00 50.00 100.00 300.00 50.00 100.00 300.0 50.00 117055-33-1117055-33-2 117055-33-3 16 mg Slow 64 mg Slow 16 mg Slow g/per g/perg/per 50 g 50 g 50 g Composition % w/w mg/tablet batch % w/w mg/tabletbatch % w/w mg/tablet batch MIN-101* 6.40 19.20 3.20 25.6 76.80 12.806.40 19.20 3.20 Hypromellose 55.00 165.00 27.50 50.00 150.00 25.00 58.00174.00 29.00 K100LV CR Mannitol M200 25.62 76.86 12.81 15.68 47.04 7.8423.52 70.56 11.76 Microcrystalline 10.98 32.94 5.49 6.72 20.16 3.3610.08 30.24 5.04 Cellulose PH102 Silica Colloidal 1.00 3.00 0.50 1.003.00 0.50 1.00 3.00 0.50 Anhydrous, Aerosil 200 Pharma Magnesium 1.003.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 stearate Total 100.00 300.0050.00 100.00 300.00 50.00 100.00 300.00 50.00 *Salt correction factor of1.2 applied.

TABLE 13 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations117055-38-1 117055-38-2 117055-38-3 117055-38-4 16 mg Slow 64 mg Slow 16mg Fast 64 mg Fast g/per g/per g/per g/per 50 g 50 g 50 g 50 gComposition % w/w mg/tablet batch % w/w mg/tablet batch % w/w mg/tabletbatch % w/w mg/tablet batch MIN-101* 6.40 19.20 3.20 25.6 76.80 12.806.40 19.20 3.20 25.60 76.80 12.80 Hypromellose 40.00 120.00 20.00 45.00135.00 22.50 25.00 75.00 12.50 20.00 60.00 10.00 K100LV CR Mannitol M20036.47 109.41 18.24 19.53 58.59 9.77 46.97 140.91 23.49 37.03 111.0918.52 Microcrystalline 15.53 46.89 7.82 8.37 25.11 4.19 20.13 60.3910.07 15.87 47.61 7.94 Cellulose PH102 Silica Colloidal 1.00 1.50 0.250.50 1.50 0.25 0.50 1.50 0.25 0.50 1.50 0.25 Anhydrous, Aerosil 200Pharma Magnesium stearate 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.501.00 3.00 0.50 Total 100.00 300.00 50.01 100.00 300.00 50.01 100.00300.00 50.01 100.00 300.00 50.01 *Salt correction factor of 1.2 applied.

TABLE 14 Analytical investigation for 64 mg MIN-101 MR tabletformulations (64 mg slow of Experiment 9) Mean Percentage ExperimentLabel Claim (%) 2 hour automatic time point (pulled through 30.3% a 10μm free flow filter) 2 hour manual time point no filtration 30.9% 19hour automatic time point (pulled through 82.0% a 10 μm fee flow filter)19 hour manual time point no filtration 82.6% 19 hour manual time pointcentrifuged 82.2% 19 hour manual time point filtered through a 82.8%0.45 μm PTFE syringe filter

TABLE 15 Compositions for 64 mg MIN-101 MR tablet formulations117055-46-1; 64 mg Slow g/per 50 Composition % w/w mg/tablet g batchMN-101* 25.6 76.80 12.80 Hypromellose K100LV CR 45.00 135.00 22.50Mannitol M200 19.53 58.59 9.77 Microcrystalline Cellulose PH102 8.3725.11 4.19 Silica Colloidal Anhydrous, 0.50 1.50 0.25 Aerosil 200 PharmaMagnesium stearate 1.00 3.00 0.50 Total 100.00 300.00 50.01 *Saltcorrection factor of 1.2 applied.

TABLE 16 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations117055-48-1 117055-48-2 117055-48-3 117055-48-4 16 mg Slow 64 mg Slow 16mg Fast 64 mg Fast g/per g/per g/per g/per 50 g 50 g 50 g 50 gComposition % w/w mg/tablet batch % w/w mg/tablet batch % w/w mg/tabletbatch % w/w mg/tablet batch MIN-101* 6.40 19.20 3.20 25.60 76.80 12.806.40 19.20 3.20 25.50 76.80 12.80 Hypromellose 55.00 165.00 27.50 50.00150.00 25.00 25.00 75.00 12.50 20.00 60.00 10.00 K100LV CR Mannitol M20025.97 77.91 12.99 16.03 48.09 8.02 46.97 140.91 23.49 37.03 111.09 18.52Microcrystalline 11.13 33.39 5.57 6.87 20.61 3.44 20.13 60.39 10.0715.87 47.61 7.94 Cellulose PH102 Sillica Colloidal 0.50 1.50 0.25 0.501.50 0.25 0.50 1.50 0.25 0.50 1.50 0.25 Anhydrous, Aerosil 200 PharmaMagnesium stearate 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.5 1.00 3.000.50 Total 100.00 300.00 50.01 100.00 300.00 50.01 100.00 300.00 50.01100.00 300.00 50.01 *Salt correction factor of 1.2 applied.

TABLE 17 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations117055-52-1 117055-52-2 16 mg Slow 64 mg Slow g/per 50 g g/per 50 gComposition % w/w mg/tablet batch % w/w mg/tablet batch MIN-101* 6.4019.20 3.20 25.60 76.80 12.80 Hypromellose K4M CR 36.00 108.00 18.0030.00 90.00 15.00 Microcrystalline Cellulose PH102 36.10 108.30 18.0522.90 68.70 11.45 Lactose Fastflo 316 20.00 60.00 10.00 20.00 60.0010.00 Sillica Colloidal Anhydrous, 0.50 1.50 0.25 0.50 1.50 0.25 Aerosil200 Pharma Magnesium stearate 1.00 3.00 0.50 1.00 3.00 0.50 Total 100.00300.00 50.00 100.00 300.00 50.01 *Salt correction factor of 1.2 applied.

TABLE 18 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations117055-54-1; 117055-54-2; 117055-54-3; 64 mg Fast 16 mg Fast 16 mg Fastg/per g/per g/per 50 g 50 g 50 g Composition % w/w mg/tablet batch % w/wmg/tablet batch % w/w mg/tablet batch MIN-101* 25.60 76.80 12.80 6.4019.20 3.20 6.40 19.20 3.20 Hypromellose K100LV CR 30.00 90.00 15.0036.00 108.00 18.00 30.00 90.00 15.00 Hypromellose K4M CR — — — — — —6.00 18.00 3.00 Microcrystalline Cellulose 22.90 68.70 11.45 36.10 108.318.05 36.10 108.3 18.05 PH102 Lactose Fastflo 316 20.00 60.00 10.0020.00 60.00 10.00 20.00 60.00 10.00 Silica Colloidal Anhydrous, 0.501.50 0.25 0.50 1.50 0.25 0.50 1.50 0.25 Aerosil 200 Pharma Magnesiumstearate 1.00 3.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 Total 100.00300.00 50.00 100.00 300.00 50.00 100.00 300.00 50.00 *Salt correctionfactor of 1.2 applied.

TABLE 19 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations117055-55-1 117055-55-2 117055-55-3 64 mg Fast 16 mg Fast 64 mg Slowg/per g/per g/per 50 g 50 g 50 g Composition % w/w mg/tablet batch % w/wmg/tablet batch % w/w mg/tablet batch MIN-101* 25.60 76.80 12.80 6.4019.20 3.20 25.60 76.80 12.80 Hypromellose 30.00 90.00 15.00 30.00 108.0018.00 6.00 18.00 3.00 K100LV CR Hypromellose — — — — — — 24.00 72.0012.00 K4M CR Microcrystalline 22.90 68.70 11.45 36.10 108.3 18.05 22.9068.70 11.45 Cellulose PH102 Lactose Fastflo 20.00 60.00 10.00 20.0060.00 10.00 20.00 60.00 10.00 316 Silica Colloidal 0.50 1.50 0.25 0.501.50 0.25 0.50 1.50 0.25 Anhydrous Aerosil 200 Pharma Magnesium 1.003.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 stearate Total 100.00 300.050.00 100.00 300.00 50.00 100.00 300.00 50.00 117055-55-4 117055-58-1117055-58-2 16 mg Slow 40 mg Medium 32 mg Slow g/per g/per g/per 50 g 50g 50 g Composition % w/w mg/tablet batch % w/w mg/tablet batch % w/wmg/tablet batch MIN-101* 6.40 19.20 3.20 16.00 48.00 8.00 12.80 38.406.40 Hypromellose 12.00 36.00 6.00 21.00 63.00 10.5 10.00 30.00 5.00K100LV CR Hypromellose 24.00 72.00 12.00 12.00 36.00 6.00 24.00 72.0012.00 K4M CR Microcrystalline 36.10 108.3 18.05 29.50 88.50 14.75 31.7095.10 15.85 Cellulose PH102 Lactose Fastflo 20.00 60.00 10.00 20.0060.00 10.00 20.00 60.00 10.00 316 Silica Colloidal 0.50 1.50 0.25 0.501.50 0.25 0.50 1.50 0.25 Anhydrous Aerosil 200 Pharma Magnesium 1.003.00 0.50 1.00 3.00 0.50 1.00 3.00 0.50 stearate Total 100.00 300.0050.00 100.00 300.00 50.00 100.00 300.00 50.00 *Salt correction factor of1.2 applied.

TABLE 20 Batch Formula for reference MIN-101 SR tablets g/per 200 gbatch Component Function % w/w mg/tablet (up to 1333 tablets)Intragranular blend MIN101 drag substance¹ Drag substance 6.40 9.6012.80 Kolliwax HCO Lubricant 20.00 30.00 40.00 Lactose (Pharmatose 200)Filler 58.93 88.40 117.86 Microcrystalline Cellulose (Vivapur 101)Filler 10.00 15.00 20.00 Hydroxypropylcellulose (HPC-L) Binder 2.80 4.205.60 Silica Colloidal Anhydrous (Aerosil 200) Glidant 0.13 0.20 0.26Citric Acid Monohydrate pH adjuster 0.67 1.00 1.34 Sterile Water forIrrigation² Process aid q.s — q.s Sub-total — 98.93 148.40 197.86Extragranular blend³ Magnesium Stearate (Hyqual) Lubricant 1.07 1.602.14 Core tablet weight — 100.00 150.00 200.00 ¹Salt conversion factorof 1.2 i.e. 9.60 mg of MIN-101 hydrochloride form drug substanceequivalent to 8.0 mg of MIN-101 free base. ²Sterile Water for Irrigationwas used for wet granulation and was removed during the drying step.³Final extragranular blend for tableting was calculated based on theyield of intragranular blend available

TABLE 21 Compositions for 16 mg and 64 mg MIN-101 MR tablet formulations(manufacturing process development) 117055-60 117055-61 117055-62 64 mgFast 16 mg Fast 64 mg Slow g/per g/per g/per mg/ 100 g mg/ 100 g mg/ 100g Composition % w/w tablet batch % w/w tablet batch % w/w tablet batchMIN-101* 25.60 76.80 25.60 6.40 19.20 6.40 25.60 76.80 25.60Hypromellose 30.00 90.00 30.00 36.00 108.00 36.00 6.00 18.00 6.00 K100LVCR Hypromellose — — — — — — 24.00 72.00 24.00 K4M CR Microcrystalline22.90 68.70 22.90 36.10 108.3 36.10 22.90 68.70 22.90 Cellulose PH102Lactose Fastflo 20.00 60.00 20.00 20.00 60.00 20.00 20.00 60.00 20.00316 Silica Colloidal 0.50 1.50 0.50 0.50 1.50 0.50 0.50 1.50 0.50Anhydrous, Aerosil 200 Pharma Magnesium 1.00 3.00 1.00 1.00 3.00 1.001.00 3.00 1.00 stearate Total 100.00 300.00 100.00 100.00 300.00 100.00100.00 300.00 100.00 117055-63 117055-64 16 mg Slow 40 mg Medium g/perg/per mg/ 100 g mg/ 100 g Composition % w/w tablet batch % w/w tabletbatch MIN-101* 6.40 19.20 6.40 16.00 48.00 16.00 Hypromellose 12.0036.00 12.00 21.00 63.00 21.00 K100LV CR Hypromellose 24.00 72.00 24.0012.00 36.00 12.00 K4M CR Microcrystalline 36.10 108.3 36.10 29.50 88.5029.50 Cellulose PH102 Lactose Fastflo 20.00 60.00 20.00 20.00 60.0020.00 316 Silica Colloidal 0.50 1.50 0.50 0.50 1.50 0.50 Anhydrous,Aerosil 200 Pharma Magnesium 1.00 3.00 1.00 1.00 3.00 1.00 stearateTotal 100.00 300.00 100.00 100.00 300.00 100.00 *Salt correction factorof 1.2 applied.

Example 4: Preparation of Form (A) of Compound (I)-HCl-2H₂O

2-((1-(2-(4-Fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one,i.e., the free base of Compound (I), is dissolved in acetone andfiltered through amorphous volcanic glass, i.e., Perlite®, to remove anyforeign matter. To this solution is added 2 mol/L-hydrochloric acidwater solution, i.e., 2 N HCl). The mixture is cooled while stirring forseveral hours and crude crystals of the hydrochloric acid salt ofCompound (I) are filtered and dried under reduced pressure. The crudecrystals are then purified by heating the crude material in acetone anddeionized water and stirring for several hours. Foreign matter is thenremoved by filtration and then additional acetone is added to thefiltrate. The mixture is cooled and the crystals are filtered and driedunder reduced pressure to provide Form (A) of Compound (I)-HCl-2H2O.

Example 5: X-Ray Powder Diffraction of Form (A) of Compound (I)HCl-2H₂O

X-ray diffractometry was performed using RIGAKU, RINT 2500. The X-raypowder diffraction of Form (A) of Compound (I)-HCl-2H₂O is shown in FIG.11 .

Example 6: IR Absorption Spectrum of Form (A) of Compound (I)HCl-2H₂O

Infrared (IR) absorption spectrometry was performed using Perkin-Elmer,Paragon1000. The IR spectrum of Form (A) of Compound (I)-HCl-2H₂O wasmeasured by a potassium chloride disk method as shown in FIG. 12 . Themain wave numbers of absorption and their assignment are as follows:

TABLE 22 Assignments of Form (A) of Compound (I) • HCl • 2H₂O IRSpectrum Wave number (cm⁻¹) Assignment 2916 C—H stretching vibration1684, 1665 C═O stretching vibration 1594 Benzene ring 1235 C—Fstretching vibration

Example 7: Nuclear Magnetic Resonance Spectrometry of Form (A) ofCompound (I)HCl-2H₂O

¹H-NMR spectrum and ¹³C-NMR spectrum of Form (A) of Compound(I)-HCl-2H₂O measured in d₆-dimethyl sulfoxide is shown in FIG. 13 andFIG. 14 , respectively.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The disclosure of the application can be embodied in other specificforms without departing from the spirit or essential characteristicsthereof. The foregoing embodiments are therefore to be considered in allrespects illustrative rather than limiting on the disclosure of theapplication described herein. Scope of the disclosure of the applicationis thus indicated by the appended claims rather than by the foregoingdescription, and all changes that come within the meaning and range ofequivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A crystalline form of Compound (I);

comprising a polymorph form (A) of Compound (I)-HCl-2H₂O, and whereinthe form (A) has a X-ray powder diffraction pattern with at least onemajor peak substantially similar to at least one major peak shown inFIG. 11 .
 2. The crystalline form of claim 1, wherein the form (A) hasX-ray powder diffraction pattern peaks at approximately 7.6 and 14.3°2θusing Cu Kα radiation.
 3. The crystalline form of claim 1 or 2, whereinthe form (A) has X-ray powder diffraction peaks at approximately 7.6,14.3, and 14.7°2θ using Cu Kα radiation.
 4. The crystalline form of anyone of claims 1-3, wherein the form (A) has X-ray powder diffractionpeaks at approximately 7.6, 14.3, and 27.5°2θ using Cu Kα radiation. 5.The crystalline form of any one of claims 1-4, wherein the form (A) hasX-ray powder diffraction peaks at approximately 7.6, 14.3, 14.7, and27.5°2θ using Cu Kα radiation.
 6. The crystalline form of any one ofclaims 1-5, wherein the form (A) has X-ray powder diffraction peaks atapproximately 7.6, 14.3, 14.7, 18.6, and 27.5°2θ using Cu Kα radiation.7. The crystalline form of any one of claims 1-6, wherein the form (A)has X-ray powder diffraction peaks at approximately 7.6, 14.3, 14.7,14.9, 18.6, 27.5 and 30.1°2θ using Cu Kα radiation.
 8. The crystallineform of any one of claims 1-7, wherein the form (A) has X-ray powderdiffraction peaks at approximately 7.6, 11.2, 14.3, 14.7, 14.9, 18.6,22.0, 25.9, 27.5 and 30.1°2θ using Cu Kα radiation.
 9. A pharmaceuticalformulation comprising Compound (I);

wherein the formulation comprises a release modifier that provides amaximum plasma concentration (C_(max)) of Compound (I) or the polymorphform (A) of Compound (I)-HCl-2H₂O below 50 ng/mL when a dose of betweenabout 1-100 mg of the formulation is administered to a human.
 10. Thepharmaceutical formulation of claim 9, when Compound (I) is present asthe polymorph form (A) of Compound (I)-HCl-2H₂O.
 11. The pharmaceuticalformulation of claim 10, comprising about 10-75 mg of Compound (I) orthe polymorph form (A) of Compound (I)-HCl-2H₂O.
 12. The pharmaceuticalformulation of claim 10, comprising about 15-65 mg of Compound (I) orthe polymorph form (A) of Compound (I)-HCl-2H₂O.
 13. The pharmaceuticalformulation of claim 10, comprising about 16 mg, about 32 mg, about 40mg, or about 64 mg of Compound (I) or the polymorph form (A) of Compound(I)-HCl-2H₂O.
 14. The pharmaceutical formulation of claim 10, whereinthe release modifier is a hypromellose.
 15. The pharmaceuticalformulation any one of claims 9-14, further comprising a filler, aglidant, and a lubricant.
 16. The pharmaceutical formulation of claim15, wherein the filler is microcrystalline cellulose, lactose, or acombination thereof.
 17. The pharmaceutical formulation of claim 15,wherein the glidant is silica colloidal anhydrous.
 18. Thepharmaceutical formulation of claim 15, wherein the lubricant ismagnesium stearate, Kolliwax HCO, sodium stearyl fumarate, or acombination thereof.
 19. The pharmaceutical formulation of any one ofclaims 9-18, wherein the formulation provides a maximum plasmaconcentration (C_(max)) of BFB-520 below 10.0 ng/mL, preferably below5.0 ng/mL.
 20. The pharmaceutical formulation of any one of claims 9-19,wherein the formulation provides a maximum plasma concentration(C_(max)) of BFB-999 below 5.0 ng/mL.
 21. The pharmaceutical formulationof any one of claims 9-20, wherein the formulation provides an AUC ofCompound (I) or the polymorph form (A) of Compound (I)-HCl-2H₂O below400 hr*ng/mL.
 22. The pharmaceutical formulation of any one of claims9-21, wherein the formulation provides an AUC of BFB-520 below 40hr*ng/mL.
 23. The pharmaceutical formulation of any one of claims 9-22,wherein the formulation provides an AUC of BFB-999 below 40 hr*ng/mL.24. The pharmaceutical formulation of any one of claims 9-23, whereinthe formulation is suitable for chronic administration.
 25. Thepharmaceutical formulation of any one of claims 9-24, wherein theformulation is in an immediate release form.
 26. The pharmaceuticalformulation of any one of claims 9-25, wherein the formulation is in acontrolled release form.
 27. The pharmaceutical formulation of any oneof claims 9-26, wherein substantially all of the administered dose ofCompound (I) or the polymorph form (A) of Compound (I)-HCl-2H₂O isreleased from the pharmaceutical formulation over 16-24 hours.
 28. Amethod of treating a neuropsychiatric disease or disorder, comprisingadministering a therapeutically effective amount of the pharmaceuticalformulation of any one of claims 9-27 to a subject in need thereof. 29.The method of claim 28, wherein the neuropsychiatric disease or disorderis schizophrenia.
 30. The method of claim 28 or 29, wherein thepharmaceutical formulation is administered once daily.
 31. The method ofany one of claims 28-30, wherein the amount of Compound (I) or thepolymorph form (A) of Compound (I)-HCl-2H₂O administered is in the rangeof about 1-100 mg.
 32. The method of claim 31, wherein the amount ofCompound (I) or the polymorph form (A) of Compound (I)-HCl-2H₂Oadministered is in the range of about 10-75 mg.
 33. The method of claim32, wherein the amount of Compound (I) or the polymorph form (A) ofCompound (I)-HCl-2H₂O administered is in the range of about 15-65 mg.34. The method of claim 31, wherein the amount of Compound (I) or thepolymorph form (A) of Compound (I)-HCl-2H₂O administered is about 16 mg,about 32 mg, about 40 mg, or about 64 mg.
 35. The method of claim 28,wherein at least one symptom of schizophrenia is treated or diminished.36. The method of claim 35, wherein the symptom is associated with thenegative and/or positive symptoms of schizophrenia, cognitive function,sleep architecture and continuity, and social functioning.
 37. Themethod of claim 28, wherein at least one condition or disorderassociated with depression is treated.
 38. A method of treating a sleepdisorder, comprising administering a therapeutically effective amount ofthe pharmaceutical formulation of any one of claims 9-37 to a subject inneed thereof.
 39. The method of claim 38, wherein at least one aspect ofa sleep disorder is treated or diminished.
 40. The method of claim 39wherein the at least one aspect of a sleep disorder is selected fromsleep period time, one or more segments of sleep period time, overallsleep continuity, and sleep architecture.
 41. The method of claim 38,wherein the sleep disorder is associated with schizophrenia.
 42. A kitcomprising the pharmaceutical formulation of any one of claims 9-41, andinstructions for use.